EC 3.4.1.1      
Transferred entry: leucyl aminopeptidase. Now EC 3.4.11.1, leucyl aminopeptidase
[EC 3.4.1.1 created 1961, deleted 1972]
 
 
EC 3.4.1.2      
Transferred entry: aminopeptidase. Now EC 3.4.11.2, membrane alanyl aminopeptidase
[EC 3.4.1.2 created 1961, deleted 1972]
 
 
EC 3.4.1.3      
Transferred entry: aminotripeptidase. Now EC 3.4.11.4, tripeptide aminopeptidase
[EC 3.4.1.3 created 1961, deleted 1972]
 
 
EC 3.4.1.4      
Transferred entry: proline iminopeptidase. Now EC 3.4.11.5, prolyl aminopeptidase
[EC 3.4.1.4 created 1965, deleted 1972]
 
 
EC 3.4.2.1      
Transferred entry: carboxypeptidase A. Now EC 3.4.17.1, carboxypeptidase A
[EC 3.4.2.1 created 1961, deleted 1972]
 
 
EC 3.4.2.2      
Transferred entry: carboxypeptidase B. Now EC 3.4.17.2, carboxypeptidase B
[EC 3.4.2.2 created 1961, deleted 1972]
 
 
EC 3.4.2.3      
Transferred entry: yeast carboxypeptidase. Now EC 3.4.17.4, Gly-Xaa carboxypeptidase
[EC 3.4.2.3 created 1961, deleted 1972]
 
 
EC 3.4.3.1      
Transferred entry: glycyl-glycine dipeptidase. Now EC 3.4.13.18, cytosol nonspecific dipeptidase
[EC 3.4.3.1 created 1961, deleted 1972]
 
 
EC 3.4.3.2      
Transferred entry: glycyl-leucine dipeptidase. Now EC 3.4.13.18, cytosol nonspecific dipeptidase
[EC 3.4.3.2 created 1961, deleted 1972]
 
 
EC 3.4.3.3      
Transferred entry: aminoacyl-histidine dipeptidase. Now EC 3.4.13.3, Xaa-His dipeptidase
[EC 3.4.3.3 created 1961, deleted 1972]
 
 
EC 3.4.3.4      
Transferred entry: aminoacyl-methylhistidine dipeptidase. Now EC 3.4.13.5, Xaa-methyl-His dipeptidase
[EC 3.4.3.4 created 1961, deleted 1972]
 
 
EC 3.4.3.5      
Transferred entry: cysteinylglycine dipeptidase. Now EC 3.4.11.2, membrane alanyl aminopeptidase
[EC 3.4.3.5 created 1961, deleted 1972]
 
 
EC 3.4.3.6      
Transferred entry: iminodipeptidase. Now EC 3.4.13.18, cytosol nonspecific dipeptidase
[EC 3.4.3.6 created 1961, deleted 1972]
 
 
EC 3.4.3.7      
Transferred entry: iminodipeptidase. Now EC 3.4.13.9, Xaa-Pro dipeptidase
[EC 3.4.3.7 created 1961, deleted 1972]
 
 
EC 3.4.4.1      
Transferred entry: pepsin. Now EC 3.4.23.1, pepsin A
[EC 3.4.4.1 created 1961, deleted 1972]
 
 
EC 3.4.4.2      
Transferred entry: pepsin B. Now EC 3.4.23.2, pepsin B
[EC 3.4.4.2 created 1961, deleted 1972]
 
 
EC 3.4.4.3      
Transferred entry: rennin. Now EC 3.4.23.4, chymosin
[EC 3.4.4.3 created 1961, deleted 1972]
 
 
EC 3.4.4.4      
Transferred entry: trypsin. Now EC 3.4.21.4, trypsin
[EC 3.4.4.4 created 1961, deleted 1972]
 
 
EC 3.4.4.5      
Transferred entry: chymotrypsin. Now EC 3.4.21.1, chymotrypsin
[EC 3.4.4.5 created 1961, deleted 1972]
 
 
EC 3.4.4.6      
Transferred entry: chymotrypsin B. Now EC 3.4.21.1, chymotrypsin
[EC 3.4.4.6 created 1961, deleted 1972]
 
 
EC 3.4.4.7      
Transferred entry: elastase. Now covered by EC 3.4.21.36, pancreatic elastase and EC 3.4.21.37, leukocyte elastase
[EC 3.4.4.7 created 1961, deleted 1972]
 
 
EC 3.4.4.8      
Transferred entry: enteropeptidase. Now EC 3.4.21.9, enteropeptidase
[EC 3.4.4.8 created 1961, deleted 1972]
 
 
EC 3.4.4.9      
Transferred entry: cathepsin C. Now EC 3.4.14.1, dipeptidyl-peptidase I
[EC 3.4.4.9 created 1961, deleted 1972]
 
 
EC 3.4.4.10      
Transferred entry: papain. Now EC 3.4.22.2, papain
[EC 3.4.4.10 created 1961, deleted 1972]
 
 
EC 3.4.4.11      
Transferred entry: chymopapain. Now EC 3.4.22.6, chymopapain
[EC 3.4.4.11 created 1961, deleted 1972]
 
 
EC 3.4.4.12      
Transferred entry: ficin. Now EC 3.4.22.3, ficain
[EC 3.4.4.12 created 1961, deleted 1972]
 
 
EC 3.4.4.13      
Transferred entry: thrombin. Now EC 3.4.21.5, thrombin
[EC 3.4.4.13 created 1961, deleted 1972]
 
 
EC 3.4.4.14      
Transferred entry: plasmin. Now EC 3.4.21.7, plasmin
[EC 3.4.4.14 created 1961, deleted 1972]
 
 
EC 3.4.4.15      
Transferred entry: renin. Now EC 3.4.23.15, renin
[EC 3.4.4.15 created 1961, deleted 1972]
 
 
EC 3.4.4.16      
Transferred entry: subtilopeptidase A. Now covered by the microbial serine proteinases EC 3.4.21.62 (subtilisin), EC 3.4.21.63 (oryzin), EC 3.4.21.64 (endopeptidase K), EC 3.4.21.65 (thermomycolin), EC 3.4.21.66 (thermitase) and EC 3.4.21.67 (ndopeptidase So)
[EC 3.4.4.16 created 1961, deleted 1972]
 
 
EC 3.4.4.17      
Transferred entry: aspergillopeptidase A. Now covered by the microbial aspartic proteinases EC 3.4.23.20 (penicillopepsin), EC 3.4.23.21 (rhizopuspepsin), EC 3.4.23.22 (endothiapepsin), EC 3.4.23.23 (mucorpepsin), EC 3.4.23.24 (candidapepsin), EC 3.4.23.25 (saccharopepsin), EC 3.4.23.26 (rhodotorulapepsin), EC 3.4.21.103 (physarolisin), EC 3.4.23.28 (acrocylindropepsin), EC 3.4.23.29 (polyporopepsin) and EC 3.4.23.30 (pycnoporopepsin)
[EC 3.4.4.17 created 1961, deleted 1972]
 
 
EC 3.4.4.18      
Transferred entry: streptococcus peptidase A. Now EC 3.4.22.10, streptopain
[EC 3.4.4.18 created 1961, deleted 1972]
 
 
EC 3.4.4.19      
Transferred entry: clostridiopeptidase A. Now EC 3.4.24.3, microbial collagenase
[EC 3.4.4.19 created 1961, deleted 1972]
 
 
EC 3.4.4.20      
Transferred entry: clostridiopeptidase B. Now EC 3.4.22.8, clostripain
[EC 3.4.4.20 created 1961, deleted 1972]
 
 
EC 3.4.4.21      
Transferred entry: kallikrein. Now EC 3.4.21.34 (plasma kallikrein) and EC 3.4.21.35 (tissue kallikrein)
[EC 3.4.4.21 created 1965, deleted 1972]
 
 
EC 3.4.4.22      
Transferred entry: now EC 3.4.23.3, gastricsin
[EC 3.4.4.22 created 1965, deleted 1972]
 
 
EC 3.4.4.23      
Transferred entry: now EC 3.4.23.5, cathepsin D
[EC 3.4.4.23 created 1965, deleted 1972]
 
 
EC 3.4.4.24      
Transferred entry: now covered by EC 3.4.22.32 (stem bromelain) and EC 3.4.22.33 (fruit bromelain)
[EC 3.4.4.24 created 1965, deleted 1972]
 
 
EC 3.4.4.25      
Deleted entry: Streptomyces alkalophilic keratinase
[EC 3.4.4.25 created 1965, deleted 1972]
 
 
EC 3.4.11.1     
Accepted name: leucyl aminopeptidase
Reaction: Release of an N-terminal amino acid, Xaa┼Yaa-, in which Xaa is preferably Leu, but may be other amino acids including Pro although not Arg or Lys, and Yaa may be Pro. Amino acid amides and methyl esters are also readily hydrolysed, but rates on arylamides are exceedingly low
Other name(s): leucine aminopeptidase; leucyl peptidase; peptidase S; cytosol aminopeptidase; cathepsin III; L-leucine aminopeptidase; leucinaminopeptidase; leucinamide aminopeptidase; FTBL proteins; proteinates FTBL; aminopeptidase II; aminopeptidase III; aminopeptidase I
Comments: A zinc enzyme isolated from pig kidney and cattle lens; activated by heavy metal ions. Type example of peptidase family M17.
References:
1.  Himmelhoch, S.R. Leucine aminopeptidase from swine kidney. Methods Enzymol. 19 (1970) 508–513.
2.  Delange, R.J. and Smith, E.L. Leucine aminopeptidase and other N-terminal exopeptidases. In: Boyer, P.D. (Ed.), The Enzymes, 3rd edn, vol. 3, Academic Press, New York, 1971, pp. 81–118.
3.  van Loon-Klaasen, L.A.H., Cuypers, H.T., van Westreenen, H., de Jong, W.W. and Bloemendal, H. The primary structure of bovine lens leucine aminopeptidase. Complete amino acid sequence of the N-terminal cyanogen bromide fragment and site limited tryptic digestion. Biochem. Biophys. Res. Commun. 95 (1980) 334–341. [PMID: 7417261]
[EC 3.4.11.1 created 1961 as EC 3.4.1.1, transferred 1972 to EC 3.4.11.1]
 
 
EC 3.4.11.2     
Accepted name: membrane alanyl aminopeptidase
Reaction: Release of an N-terminal amino acid, Xaa┼Yaa- from a peptide, amide or arylamide. Xaa is preferably Ala, but may be most amino acids including Pro (slow action). When a terminal hydrophobic residue is followed by a prolyl residue, the two may be released as an intact Xaa-Pro dipeptide
Other name(s): microsomal aminopeptidase; aminopeptidase M; aminopeptidase N; particle-bound aminopeptidase; amino-oligopeptidase; alanine aminopeptidase; membrane aminopeptidase I; pseudo leucine aminopeptidase; alanyl aminopeptidase; alanine-specific aminopeptidase; cysteinylglycine dipeptidase; cysteinylglycinase; L-alanine aminopeptidase; CD13
Comments: A zinc enzyme, not activated by heavy metal ions. Type example of peptidase family M1.
References:
1.  Wachsmuth, D., Fritze, I. and Pfleiderer, G. An aminopeptidase occurring in pig kidney. I. An improved method of preparation. Physical and enzymatic properties. Biochemistry 5 (1966) 169–174. [PMID: 5938934]
2.  Kim, Y.S. and Brophy, E.J. Rat intestinal brush border membrane peptidases. I. Solubilization, purification of two different forms of enzyme. J. Biol. Chem. 251 (1976) 3199–3205. [PMID: 931983]
3.  Gray, G.M. and Santiago, N.A. Intestinal surface amino-oligopeptidases. I. Isolation of two weight isomers and their subunits from rat brush border. J. Biol. Chem. 252 (1977) 4922–4928. [PMID: 873921]
4.  Sjöström, H., Norén, O., Jeppesen, L., Staun, M., Svensson, B. and Christiansen, L. Purification of different amphiphilic forms of a microvillus aminopeptidase from pig small intestine using immunoadsorbent chromatography. Eur. J. Biochem. 88 (1978) 503–511. [PMID: 357150]
5.  Ferracci, H. and Maroux, S. Rabbit intestinal aminopeptidase N. Purification and molecular properties. Biochim. Biophys. Acta 599 (1980) 448–463. [PMID: 6105876]
[EC 3.4.11.2 created 1961 as EC 3.4.1.2, transferred 1972 to EC 3.4.11.2 (EC 3.4.13.6 created 1961 as EC 3.4.3.5, transferred 1972 to EC 3.4.13.6, incorporated 1997)]
 
 
EC 3.4.11.3     
Accepted name: cystinyl aminopeptidase
Reaction: Release of an N-terminal amino acid, Cys┼Xaa-, in which the half-cystine residue is involved in a disulfide loop, notably in oxytocin or vasopressin. Hydrolysis rates on a range of aminoacyl arylamides exceed that for the cystinyl derivative, however [4]
Other name(s): cystyl-aminopeptidase; oxytocinase; cystine aminopeptidase; L-cystine aminopeptidase; oxytocin peptidase; vasopresssinase
Comments: A zinc-containing sialoglycoprotein in peptidase family M1 (membrane alanyl aminopeptidase family)
References:
1.  Sjöholm, I. Biochemical studies on oxytocin and oxytocinase. Acta Pharm. Suec. 4 (1967) 81–96. [PMID: 6041057]
2.  Sjöholm, I. and Yman, L. Degradation of oxytocin, lysine vasopressin, angiotensin II, and angiotensin II amide by oxytocinase (cystine aminopeptidase). Acta Pharm. Suec. 4 (1967) 65–76. [PMID: 4292447]
3.  Yman, L. Studies on human serum aminopeptidase. Some properties of oxytocinase, human serum aminopeptidase A and leucine aminopeptidase and their purification from retroplacental serum. Acta Pharm. Suec. 7 (1970) 75–86. [PMID: 5421622]
4.  Sakura, H., Lin, T.Y., Doi, M., Mizutani, S. and Kawashima, Y. Purification and properties of oxytocinase, a metalloenzyme. Biochem. Int. 2 (1981) 173–179.
[EC 3.4.11.3 created 1972]
 
 
EC 3.4.11.4     
Accepted name: tripeptide aminopeptidase
Reaction: Release of the N-terminal residue from a tripeptide
Other name(s): tripeptidase; aminotripeptidase; aminoexotripeptidase; lymphopeptidase; imidoendopeptidase; peptidase B; alanine-phenylalanine-proline arylamidase; peptidase T
Comments: A zinc enzyme, widely distributed in mammalian tissues. Formerly EC 3.4.1.3
References:
1.  Doumeng, C. and Maroux, S. Aminopeptidase, a cytosol enzyme from rabbit intestinal mucosa. Biochem. J. 177 (1979) 801–808. [PMID: 109082]
2.  Sachs, L. and Marks, N. A highly specific aminotripeptidase of rat brain cytosol. Substrate specifity and effects of inhibitors. Biochim. Biophys. Acta 706 (1982) 229–238. [PMID: 7126601]
[EC 3.4.11.4 created 1961 as EC 3.4.1.3, transferred 1972 to EC 3.4.11.4]
 
 
EC 3.4.11.5     
Accepted name: prolyl aminopeptidase
Reaction: Release of N-terminal proline from a peptide
Other name(s): proline aminopeptidase; Pro-X aminopeptidase; cytosol aminopeptidase V; proline iminopeptidase
Comments: A Mn2+-requiring enzyme present in the cytosol of mammalian and microbial cells. In contrast to the mammalian form, the bacterial form of the enzyme (type example of peptidase family S33) hydrolyses both polyproline and prolyl-2-naphthylamide. The mammalian enzyme, which is not specific for prolyl bonds, is possibly identical with EC 3.4.11.1, leucyl aminopeptidase.
References:
1.  Sarid, S., Berger, A. and Katchalski, E. Proline iminopeptidase. II. Purification and comparison with iminopeptidase (prolinase). J. Biol. Chem. 237 (1962) 2207–2212. [PMID: 14497218]
2.  Nordwig, A. and Mayer, H. The cleavage of prolyl peptidases by kidney peptidases. Hoppe-Seyler's Z. Physiol. Chem. 354 (1973) 380–383. [PMID: 4803482]
3.  Turzynski, A. and Mentlein, R. Prolyl aminopeptidase from rat brain and kidney. Action on peptides and identification as leucyl aminopeptidase. Eur. J. Biochem. 190 (1990) 509–515. [PMID: 2373079]
[EC 3.4.11.5 created 1965 as EC 3.4.1.4, transferred 1972 to EC 3.4.11.5]
 
 
EC 3.4.11.6     
Accepted name: aminopeptidase B
Reaction: Release of N-terminal Arg and Lys from oligopeptides when P1′ is not Pro. Also acts on arylamides of Arg and Lys
Glossary: amastatin = Leu[1Ψ2,CHOHCONH]ValValAsp
arphamenine A = Arg[1Ψ2,COCH2]Phe
arphamenine B = Arg[1Ψ2,COCH2]Tyr
bestatin = Phe[1Ψ2,CHOHCONH]Leu
Other name(s): arylamidase II; arginine aminopeptidase; arginyl aminopeptidase; Cl--activated arginine aminopeptidase; cytosol aminopeptidase IV; L-arginine aminopeptidase
Comments: Cytosolic or membrane-associated enzyme from mammalian tissues, activated by chloride ions and low concentrations of thiol compounds. This is one of the activities of the bifunctional enzyme EC 3.3.2.6 (membrane alanyl aminopeptidase family) [4,5].
References:
1.  Gainer, H., Russell, J.T. and Loh, Y.P. An aminopeptidase activity in bovine pituitary secretory vesicles that cleaves the N-terminal arginine from β-lipotropin(60-65). FEBS Lett. 175 (1984) 135–139. [PMID: 6434344]
2.  Belhacène, N., Mari, B., Rossi, B. and Auberger, P. Characterization and purification of T lymphocyte aminopeptidase B: a putative marker of T cell activation. Eur. J. Immunol. 23 (1993) 1948–1955. [PMID: 8344358]
3.  Cadel, S., Pierotti, A.R., Foulon, T., Créminon, C., Barré, N., Segrétain, D. and Cohen, P. Aminopeptidase-B in the rat testes: Isolation, functional properties and cellular localization in the seminiferous tubules. Mol. Cell. Endocrinol. 110 (1995) 149–160. [PMID: 7672445]
4.  Fukasawa, K.M., Fukasawa, K., Kanai, M., Fujii, S. and Harada, M. Molecular cloning and expression of rat liver aminopeptidase B. J. Biol. Chem. 271 (1996) 30731–30735. [PMID: 8940051]
5.  Cadel, S., Foulon, T., Viron, A., Balogh, A., Midol-Monnet, S., Noel, N. and Cohen, P. Aminopeptidase B from the rat testis is a bifunctional enzyme structually related to leukotriene-A4 hydrolase. Proc. Natl. Acad. Sci. USA 94 (1997) 2963–2968. [PMID: 9096329]
6.  Orning, L., Gierse, J.K. and Fitzpatrick, F.A. The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J. Biol. Chem. 269 (1994) 11269. [PMID: 8157657]
[EC 3.4.11.6 created 1972, modified 1997]
 
 
EC 3.4.11.7     
Accepted name: glutamyl aminopeptidase
Reaction: Release of N-terminal glutamate (and to a lesser extent aspartate) from a peptide
Other name(s): aminopeptidase A; aspartate aminopeptidase; angiotensinase A; glutamyl peptidase; Ca2+-activated glutamate aminopeptidase; membrane aminopeptidase II; antigen BP-1/6C3 of mouse B lymphocytes; L-aspartate aminopeptidase; angiotensinase A2
Comments: Ca2+-activated and generally membrane-bound. A zinc-metallopeptidase in family M1 (membrane alanyl aminopeptidase family)
References:
1.  Glenner, G.G., McMillan, P.J. and Folk, J.E. A mammalian peptidase specific for the hydrolysis of N-terminal α-L-glutamyl and aspartyl residues. Nature 194 (1962) 867. [PMID: 13899213]
2.  Chulkova, T.M. and Orekhovich, V.N. Isolation and properties of aminopeptidase A from bovine kidneys. Biokhimiya 43 (1978) 964–969. [PMID: 508862]
3.  Danielsen, E.M., Norén, O., Sjöström, H., Ingram, J. and Kenny, J. Proteins of the kidney microvillar membrane. Aspartate aminopeptidase: purification by immunoadsorbent chromatography and properties of the detergent- and proteinase-solubilized forms. Biochem. J. 189 (1980) 591–603. [PMID: 7011318]
4.  Tobe, H., Kojima, F., Aoyagi, T. and Umezawa, H. Purification by affinity chromatography using amastatin and properties of aminopeptidase A from pig kidney. Biochim. Biophys. Acta 613 (1980) 459–468. [PMID: 7448199]
5.  Wu, Q., Lahti, J.M., Air, G.M., Burrows, P.D. and Cooper, M.D. Molecular cloning of the murine BP-1/6C3 antigen: a member of the zinc-dependent metallopeptidase family. Proc. Natl Acad. Sci. USA 87 (1990) 993–997. [PMID: 1689065]
[EC 3.4.11.7 created 1972]
 
 
EC 3.4.11.8      
Transferred entry: pyroglutamyl aminopeptidase. Now EC 3.4.19.3, pyroglutamyl-peptidase I
[EC 3.4.11.8 created 1972, deleted 1981]
 
 
EC 3.4.11.9     
Accepted name: Xaa-Pro aminopeptidase
Reaction: Release of any N-terminal amino acid, including proline, that is linked to proline, even from a dipeptide or tripeptide
Other name(s): proline aminopeptidase; aminopeptidase P; aminoacylproline aminopeptidase; X-Pro aminopeptidase
Comments: A Mn2+-dependent, generally membrane-bound enzyme present in both mammalian and bacterial cells. In peptidase family M24 (methionyl aminopeptidase family)
References:
1.  Yaron, A. and Mlynar, D. Aminopeptidase-P. Biochem. Biophys. Res. Commun. 32 (1968) 658–663. [PMID: 4878817]
2.  Yaron, A. and Berger, A. Aminopeptidase-P. Methods Enzymol. 19 (1970) 522–534.
3.  Fleminger, G., Carmel, A. and Yaron, A. Fluorogenic substrates for bacterial aminopeptidase P and its analogs detected in human serum and calf lung. Eur. J. Biochem. 125 (1982) 609–615. [PMID: 6749499]
4.  Orawski, A.T., Susz, J.P. and Simmons, W.H. Aminopeptidase-P from bovine lung - solubilization, properties, potential role in bradykinin degradation. Mol. Cell. Biochem. 75 (1987) 123–132. [PMID: 3627107]
5.  Hooper, N.M., Hryszko, J. and Turner, A.J. Purification and characterization of pig kidney aminopeptidase P. Biochem. J. 267 (1990) 509–515. [PMID: 2139778]
[EC 3.4.11.9 created 1972]
 
 
EC 3.4.11.10     
Accepted name: bacterial leucyl aminopeptidase
Reaction: Release of an N-terminal amino acid, preferentially leucine, but not glutamic or aspartic acids
Other name(s): Aeromonas proteolytica aminopeptidase
Comments: A zinc enzyme. Forms of the enzyme have been isolated from Aeromonas proteolytica, Escherichia coli and Streptococcus thermophilus. Examples are known from peptidase families M17 and M28 (of leucyl aminopeptidase and aminopeptidase Y, respectively)
References:
1.  Prescott, J.M. and Wilkes, S.H. Aeromonas aminopeptidase: purification and some general properties. Arch. Biochem. Biophys. 117 (1966) 328–336. [PMID: 4961737]
2.  Dick, A.J., Matheson, A.T. and Wang, J.H. A ribosomal-bound aminopeptidase in Escherichia coli B: purification and properties. Can. J. Biochem. 48 (1970) 1181–1188. [PMID: 4920230]
3.  Rabier, D. and Desmazeaud, M.J. Inventaire des différentes activités peptidasiques intracellulaires de Streptococcus thermophilus. Purification et propriétés d’une dipeptide-hydrolase et d’une aminopeptidase. Biochimie 55 (1973) 389–404. [PMID: 4749719]
[EC 3.4.11.10 created 1972]
 
 
EC 3.4.11.11      
Deleted entry:  aminopeptidase
[EC 3.4.11.11 created 1978, deleted 1992]
 
 
EC 3.4.11.12      
Deleted entry:  thermophilic aminopeptidase
[EC 3.4.11.12 created 1978, deleted 1997]
 
 
EC 3.4.11.13     
Accepted name: clostridial aminopeptidase
Reaction: Release of any N-terminal amino acid, including proline and hydroxyproline, but no cleavage of Xaa-Pro-
Other name(s): Clostridium histolyticum aminopeptidase
Comments: A secreted enzyme from Clostridium histolyticum, requiring Mn2+ or Co2+
References:
1.  Kessler, E. and Yaron, A. A novel aminopeptidase from Clostridium histolyticum. Biochem. Biophys. Res. Commun. 50 (1973) 405–412. [PMID: 4631895]
2.  Kessler, E. and Yaron, A. An extracellular aminopeptidase from Clostridium histolyticum. Eur. J. Biochem. 63 (1976) 271–287. [PMID: 4318]
3.  Kessler, E. and Yaron, A. Extracellular aminopeptidase from Clostridium histolyticum. Methods Enzymol. 45 (1976) 544–552. [PMID: 13266]
[EC 3.4.11.13 created 1978]
 
 
EC 3.4.11.14     
Accepted name: cytosol alanyl aminopeptidase
Reaction: Release of an N-terminal amino acid, preferentially alanine, from a wide range of peptides, amides and arylamides
Other name(s): arylamidase; aminopolypeptidase; thiol-activated aminopeptidase; human liver aminopeptidase; puromycin-sensitive aminopeptidase; soluble alanyl aminopeptidase; cytosol aminopeptidase III; alanine aminopeptidase
Comments: A puromycin-sensitive, Co2+-activated zinc-sialoglycoprotein that is generally cytosolic. Multiple forms are widely distributed in mammalian tissues and body fluids. In peptidase family M1 (membrane alanyl aminopeptidase family)
References:
1.  Starnes, W.L. and Behal, F.J. A human liver aminopeptidase. The amino acid and carbohydrate content, and some physical properties of a sialic acid containing glycoprotein. Biochemistry 13 (1974) 3221–3227. [PMID: 4841062]
2.  Kao, Y.J., Starnes, W.L. and Behal, F.J. Human kidney alanine aminopeptidase: physical and kinetic properties of a sialic acid containing glycoprotein. Biochemistry 17 (1978) 2990–2994. [PMID: 698181]
3.  Sidorowicz, W., Hsia, W.-C., Maslej-Zownir, M. and Behal, F.J. Multiple molecular forms of human alanine aminopeptidase: imunochemical properties. Clin. Chim. Acta 107 (1980) 245–256. [PMID: 6108169]
[EC 3.4.11.14 created 1978]
 
 
EC 3.4.11.15     
Accepted name: aminopeptidase Y
Reaction: Preferentially, release of N-terminal lysine
Other name(s): aminopeptidase Co; aminopeptidase (cobalt-activated); lysyl aminopeptidase
Comments: Requires Co2+; inhibited by Zn2+ and Mn2+. An enzyme best known from Saccharomyces cerevisiae that hydrolyses Lys-NHPhNO2 and, more slowly, Arg-NHPhNO2. Type example of peptidase family M28
References:
1.  Achstetter, T., Ehmann, C. and Wolf, D.H. Aminopeptidase Co, a new yeast peptidase. Biochem. Biophys. Res. Commun. 109 (1982) 341–347. [PMID: 6758786]
2.  Yasuhara, T., Nakai, T. and Ohashi, A. Aminopeptidase Y, a new aminopeptidase from Saccharomyces cerevisiae. Purification, properties, localization, and processing by protease B. J. Biol. Chem. 269 (1994) 13644–13650. [PMID: 8175799]
3.  Nishizawa, M., Yasuhara, T., Nakai, T., Fujiki, Y. and Ohashi, A. Molecular cloning of the aminopeptidase Y gene of Saccharomyces cerevisiae. Sequence analysis and gene disruption of a new aminopeptidase. J. Biol. Chem. 269 (1994) 13651–13655. [PMID: 8175800]
[EC 3.4.11.15 created 1989, modified 1997]
 
 
EC 3.4.11.16     
Accepted name: Xaa-Trp aminopeptidase
Reaction: Release of a variety of N-terminal residues (especially glutamate and leucine) from peptides, provided tryptophan (or at least phenylalanine or tyrosine) is the penultimate residue. Also acts on Glu┼Trp, Leu┼Trp and a number of other dipeptides
Other name(s): aminopeptidase W; aminopeptidase X-Trp; X-Trp aminopeptidase
Comments: A glycoprotein containing Zn2+, from renal and intestinal brush border membranes
References:
1.  Gee, N.S. and Kenny, A.J. Proteins of the kidney microvillar membrane. The 130kDa protein in pig kidney, recognised by monoclonal antibody GK5C1, is an ectoenzyme with aminopeptidase activity. Biochem. J. 230 (1985) 753–764. [PMID: 4062876]
2.  Gee, N.S. and Kenny, A.J. Proteins of the kidney microvillar membrane. Enzymic and molecular properties of aminopeptidase W. Biochem. J. 246 (1987) 97–102. [PMID: 2890346]
[EC 3.4.11.16 created 1989]
 
 
EC 3.4.11.17     
Accepted name: tryptophanyl aminopeptidase
Reaction: Preferential release of N-terminal tryptophan
Other name(s): tryptophan aminopeptidase; L-tryptophan aminopeptidase
Comments: From Trichosporon cutaneum. Also acts on L-tryptophanamide. Requires Mn2+
References:
1.  Iwayama, A., Kimura, T., Adachi, O. and Ameyama, M. Crystallization and characterization of a novel aminopeptidase from Trichosporon cutaneum. Agric. Biol. Chem. 47 (1983) 2483–2493.
[EC 3.4.11.17 created 1989]
 
 
EC 3.4.11.18     
Accepted name: methionyl aminopeptidase
Reaction: Release of N-terminal amino acids, preferentially methionine, from peptides and arylamides
Other name(s): methionine aminopeptidase; peptidase M; L-methionine aminopeptidase; MAP
Comments: This membrane-bound enzyme, which is present in both prokaryotes and eukaryotes, releases the initiator methionine from nascent peptides. The activity is dependent on the identity of the second, third and fourth amino acid residues of the target protein, but in general the enzyme acts only when the penultimate residue is small and uncharged (e.g. Gly, Ala, Cys, Ser, Thr, and Val).
References:
1.  Yoshida, A. and Lin, M. NH2-terminal formylmethionine- and NH2-terminal methionine-cleaving enzymes in rabbits. J. Biol. Chem. 247 (1972) 952–957. [PMID: 4110013]
2.  Tsunasawa, S., Stewart, J.W. and Sherman, F. Acylamino acid-releasing enzyme from rat liver. J. Biol. Chem. 260 (1985) 5832. [PMID: 2985590]
3.  Freitas, J.O., Jr., Termignoni, C. and Guimaraes, J.A. Methionine aminopeptidase associated with liver mitochondria and microsomes. Int. J. Biochem. 17 (1985) 1285–1291. [PMID: 3937747]
4.  Ben-Bassat, A., Bauer, K., Chang, S.-Y., Myambo, K., Boosman, A. and Chang, S. Processing of the initiation methionine from proteins: properties of Escherichia coli methionine aminopeptidase and its gene structure. J. Bacteriol. 169 (1987) 751–757. [PMID: 3027045]
5.  Roderick, S.L. and Matthews, B.W. Crystallization of methionine aminopeptidase from Escherichia coli. J. Biol. Chem. 263:16531 (1988). [PMID: 3141408]
[EC 3.4.11.18 created 1990]
 
 
EC 3.4.11.19     
Accepted name: D-stereospecific aminopeptidase
Reaction: Release of an N-terminal D-amino acid from a peptide, Xaa┼Yaa-, in which Xaa is preferably D-Ala, D-Ser or D-Thr. D-Amino acid amides and methyl esters also are hydrolysed, as is glycine amide
Other name(s): D-aminopeptidase
Comments: Known from the bacterium Ochrobactrum anthropi. In peptidase family S12 (D-Ala-D-Ala carboxypeptidase family) [2]
References:
1.  Asano, Y., Nakazawa, A., Kato, Y. and Kondo, K. Properties of a novel D-stereospecific aminopeptidase from Ochrobactrum anthropi. J. Biol. Chem. 264 (1989) 14233–14239. [PMID: 2760064]
2.  Asano, Y., Kato, Y., Yamada, A. and Kondo, K. Structural similarity of D-aminopeptidase to carboxypeptidase DD and β-lactamases. Biochemistry 31 (1992) 2316–2328. [PMID: 1540587]
[EC 3.4.11.19 created 1993]
 
 
EC 3.4.11.20     
Accepted name: aminopeptidase Ey
Reaction: Differs from other aminopeptidases in broad specificity for amino acids in the P1 position and the ability to hydrolyse peptides of four or five residues that contain Pro in the P1′ position
Comments: A zinc glycoprotein in peptidase family M1 (membrane alanyl aminopeptidase family), composed of two 150 kDa subunits. From the plasma fraction of hen egg yolk
References:
1.  Ichishima, E., Yamagata, Y., Chiba, H., Sawaguchi, K. and Tanaka, T. Soluble and bound forms of aminopeptidase in hens egg-yolk. Agric. Biol. Chem. 53 (1989) 1867–1872.
2.  Tanaka, T. and Ichishima, E. Substrate specificity of aminopeptidase Ey from hen's egg yolk. Comp. Biochem. Physiol. [B] 105 (1993) 105–110. [PMID: 7684960]
3.  Tanaka, T. and Ichishima, E. Molecular properties of aminopeptidase Ey as a zinc-metalloenzyme. Int. J. Biochem. 25 (1993) 1681–1688. [PMID: 8288037]
[EC 3.4.11.20 created 1995]
 
 
EC 3.4.11.21     
Accepted name: aspartyl aminopeptidase
Reaction: Release of an N-terminal aspartate or glutamate from a peptide, with a preference for aspartate
Comments: Aminoacyl-arylamides are poor substrates. This is an abundant cytosolic enzyme in mammalian cells, in peptidase family M18 of aminopeptidase I
References:
1.  Kelly, J.A., Neidle, E.L. and Neidle, A. An aminopeptidase from mouse brain cytosol that cleaves N-terminal acidic amino acid residues. J. Neurochem. 40 (1983) 1727–1734. [PMID: 6854330]
2.  Wilk, S., Wilk, E. and Magnusson, R.P. Purification, characterization and cloning of a cytosolic aspartyl aminopeptidase. J. Biol. Chem. 273 (1998) 15961–15970. [PMID: 9632644]
[EC 3.4.11.21 created 2000]
 
 
EC 3.4.11.22     
Accepted name: aminopeptidase I
Reaction: Release of an N-terminal amino acid, preferably a neutral or hydrophobic one, from a polypeptide. Aminoacyl-arylamides are poor substrates
Other name(s): aminopeptidase III; aminopeptidase yscI; leucine aminopeptidase IV; yeast aminopeptidase I
Comments: A 640-kDa, dodecameric enzyme best known as the major vacuolar aminopeptidase of yeast, Saccharomyces cervisiae, in which species it was first given the name aminopeptidase I (one), amongst others. Activity is stimulated by both Zn2+ and Cl- ions. Type example of peptidase family M18
References:
1.  Johnson, M.J. Isolation and properties of a pure yeast polypeptidase. J. Biol. Chem. 137 (1941) 575–586.
2.  Metz, G. and Rohm, K.-H. Yeast aminopeptidase I. Chemical composition and catalytic properties. Biochim. Biophys. Acta 429 (1976) 933–949. [PMID: 5147]
3.  Chang, Y-H. and Smith, J.A. Molecular cloning and sequencing of genomic DNA encoding aminopeptidase I from Saccharomyces cerevisiae. J. Biol. Chem. 264 (1989) 6979–6983. [PMID: 2651436]
4.  Oda, M.N., Scott, S.V., Hefner-Gravink, A., Caffarelli, A.D. and Klionsky, D.J. Identification of a cytoplasm to vacuole targeting determinant in aminopeptidase I. J. Cell Biol. 132 (1996) 999–1010. [PMID: 8601598]
[EC 3.4.11.22 created 1997]
 
 
EC 3.4.11.23     
Accepted name: PepB aminopeptidase
Reaction: Release of an N-terminal amino acid, Xaa, from a peptide or arylamide. Xaa is preferably Glu or Asp but may be other amino acids, including Leu, Met, His, Cys and Gln
Other name(s): Salmonella enterica serovar Typhimurium peptidase B
Comments: A 270-kDa protein composed of six 46.3-kDa subunits. The pH optimum is in the alkaline range and activity is stimulated by KCl. In peptidase family M17.
References:
1.  Mathew, Z., Knox, T.M. and Miller, C.G. Salmonella enterica serovar typhimurium peptidase B is a leucyl aminopeptidase with specificity for acidic amino acids. J. Bacteriol. 182 (2000) 3383–3393. [PMID: 10852868]
[EC 3.4.11.23 created 2003]
 
 
EC 3.4.11.24     
Accepted name: aminopeptidase S
Reaction: Release of an N-terminal amino acid with a preference for large hydrophobic amino-terminus residues
Other name(s): Mername-AA022 peptidase; SGAP; aminopeptidase (Streptomyces griseus); Streptomyces griseus aminopeptidase; S. griseus AP; double-zinc aminopeptidase
Comments: Aminopeptidases are associated with many biological functions, including protein maturation, protein degradation, cell-cycle control and hormone-level regulation [3,4]. This enzyme contains two zinc molecules in its active site and is activated by Ca2+ [4]. In the presence of Ca2+, the best substrates are Leu-Phe, Leu-Ser, Leu-pNA (aminoacyl-p-nitroanilide), Phe-Phe-Phe and Phe-Phe [3]. Peptides with proline in the P1′ position are not substrates [3]. Belongs in peptidase family M28.
References:
1.  Spungin, A. and Blumberg, S. Streptomyces griseus aminopeptidase is a calcium-activated zinc metalloprotein. Purification and properties of the enzyme. Eur. J. Biochem. 183 (1989) 471–477. [PMID: 2503378]
2.  Ben-Meir, D., Spungin, A., Ashkenazi, R. and Blumberg, S. Specificity of Streptomyces griseus aminopeptidase and modulation of activity by divalent metal ion binding and substitution. Eur. J. Biochem. 212 (1993) 107–112. [PMID: 8444149]
3.  Arima, J., Uesugi, Y., Iwabuchi, M. and Hatanaka, T. Study on peptide hydrolysis by aminopeptidases from Streptomyces griseus, Streptomyces septatus and Aeromonas proteolytica. Appl. Microbiol. Biotechnol. 70 (2006) 541–547. [PMID: 16080009]
4.  Fundoiano-Hershcovitz, Y., Rabinovitch, L., Langut, Y., Reiland, V., Shoham, G. and Shoham, Y. Identification of the catalytic residues in the double-zinc aminopeptidase from Streptomyces griseus. FEBS Lett. 571 (2004) 192–196. [PMID: 15280041]
5.  Gilboa, R., Greenblatt, H.M., Perach, M., Spungin-Bialik, A., Lessel, U., Wohlfahrt, G., Schomburg, D., Blumberg, S. and Shoham, G. Interactions of Streptomyces griseus aminopeptidase with a methionine product analogue: a structural study at 1.53 Å resolution. Acta Crystallogr. D Biol. Crystallogr. 56 (2000) 551–558. [PMID: 10771423]
[EC 3.4.11.24 created 2008]
 
 
EC 3.4.11.25     
Accepted name: β-peptidyl aminopeptidase
Reaction: Cleaves N-terminal β-homoamino acids from peptides composed of 2 to 6 amino acids
Other name(s): BapA (ambiguous)
Comments: Sphingosinicella xenopeptidilytica strain 3-2W4 is able to utilize the β-peptides β-homoVal-β-homoAla-β-homoLeu and β-homoAla-β-homoLeu as sole carbon and energy sources [2].
References:
1.  Heck, T., Limbach, M., Geueke, B., Zacharias, M., Gardiner, J., Kohler, H.P. and Seebach, D. Enzymatic degradation of β- and mixed α,β-oligopeptides. Chem. Biodivers. 3 (2006) 1325–1348. [PMID: 17193247]
2.  Geueke, B., Namoto, K., Seebach, D. and Kohler, H.P. A novel β-peptidyl aminopeptidase (BapA) from strain 3-2W4 cleaves peptide bonds of synthetic β-tri- and β-dipeptides. J. Bacteriol. 187 (2005) 5910–5917. [PMID: 16109932]
3.  Geueke, B., Heck, T., Limbach, M., Nesatyy, V., Seebach, D. and Kohler, H.P. Bacterial β-peptidyl aminopeptidases with unique substrate specificities for β-oligopeptides and mixed β,α-oligopeptides. FEBS J. 273 (2006) 5261–5272. [PMID: 17064315]
4.  Heck, T., Kohler, H.P., Limbach, M., Flögel, O., Seebach, D. and Geueke, B. Enzyme-catalyzed formation of β-peptides: β-peptidyl aminopeptidases BapA and DmpA acting as β-peptide-synthesizing enzymes. Chem. Biodivers. 4 (2007) 2016. [PMID: 17886858]
[EC 3.4.11.25 created 2011]
 
 
EC 3.4.11.26     
Accepted name: intermediate cleaving peptidase 55
Reaction: The enzyme cleaves the Pro36-Pro37 bond of cysteine desulfurase (EC 2.8.1.7) removing three amino acid residues (Tyr-Ser-Pro) from the N-terminus after cleavage by mitochondrial processing peptidase.
Other name(s): Icp55; mitochondrial intermediate cleaving peptidase 55 kDa
Comments: Icp55 removes the destabilizing N-terminal amino acid residues that are left after cleavage by the mitochondrial processing peptidase, leading to the stabilisation of the substrate. The enzyme can remove single amino acids or a short peptide, as in the case of cysteine desulfurase (EC 2.8.1.7), where three amino acids are removed.
References:
1.  Naamati, A., Regev-Rudzki, N., Galperin, S., Lill, R. and Pines, O. Dual targeting of Nfs1 and discovery of its novel processing enzyme, Icp55. J. Biol. Chem. 284 (2009) 30200–30208. [PMID: 19720832]
2.  Vogtle, F.N., Wortelkamp, S., Zahedi, R.P., Becker, D., Leidhold, C., Gevaert, K., Kellermann, J., Voos, W., Sickmann, A., Pfanner, N. and Meisinger, C. Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability. Cell 139 (2009) 428–439. [PMID: 19837041]
[EC 3.4.11.26 created 2011]
 
 
EC 3.4.12.1      
Transferred entry: now EC 3.4.16.5 (carboxypeptidase C) and EC 3.4.16.6 (carboxypeptidase D)
[EC 3.4.12.1 created 1972, deleted 1978]
 
 
EC 3.4.12.2      
Transferred entry: now EC 3.4.17.1, carboxypeptidase A
[EC 3.4.12.2 created 1972, deleted 1978]
 
 
EC 3.4.12.3      
Transferred entry: now EC 3.4.17.2, carboxypeptidase B
[EC 3.4.12.3 created 1972, deleted 1978]
 
 
EC 3.4.12.4      
Transferred entry: now EC 3.4.16.2, lysosomal Pro-Xaa carboxypeptidase
[EC 3.4.12.4 created 1972, modified 1976, deleted 1978]
 
 
EC 3.4.12.5      
Transferred entry: now EC 3.5.1.28, N-acetylmuramoyl-L-alanine amidase
[EC 3.4.12.5 created 1972, deleted 1978]
 
 
EC 3.4.12.6      
Transferred entry: now EC 3.4.17.8, muramoyl-pentapeptidase carboxypeptidase
[EC 3.4.12.6 created 1972, deleted 1978]
 
 
EC 3.4.12.7      
Transferred entry: now EC 3.4.17.3, lysine carboxypeptidase
[EC 3.4.12.7 created 1972, deleted 1978]
 
 
EC 3.4.12.8      
Transferred entry: now EC 3.4.17.4, Gly-Xaa carboxypeptidase
[EC 3.4.12.8 created 1972, deleted 1978]
 
 
EC 3.4.12.9      
Deleted entry: aspartate carboxypeptidase
[EC 3.4.12.9 created 1972, deleted 1978]
 
 
EC 3.4.12.10      
Transferred entry: now EC 3.4.19.9, γ-glutamyl hydrolase
[EC 3.4.12.10 created 1972, modified 1976, deleted 1978]
 
 
EC 3.4.12.11      
Transferred entry: now EC 3.4.17.6, alanine carboxypeptidase
[EC 3.4.12.11 created 1972, deleted 1978]
 
 
EC 3.4.12.12      
Transferred entry: now EC 3.4.16.5 (carboxypeptidase C) and EC 3.4.16.6 (carboxypeptidase D)
[EC 3.4.12.12 created 1972, deleted 1978]
 
 
EC 3.4.12.13      
Deleted entry: γ-glutamylglutamate carboxypeptidase
[EC 3.4.12.13 created 1975, modified 1976, deleted 1978]
 
 
EC 3.4.13.1      
Transferred entry: glycyl-glycine dipeptidase. Now EC 3.4.13.18, cytosol nonspecific dipeptidase
[EC 3.4.13.1 created 1972, deleted 1978 [transferred to EC 3.4.13.11, deleted 1992]]
 
 
EC 3.4.13.2      
Transferred entry: glycyl-leucine dipeptidase. Now EC 3.4.13.18, cytosol nonspecific dipeptidase
[EC 3.4.13.2 created 1972, deleted 1978 [transferred to EC 3.4.13.11, deleted 1992]]
 
 
EC 3.4.13.3      
Deleted entry: Xaa-His dipeptidase. The activity is covered by EC 3.4.13.18, cytosol nonspecific dipeptidase and EC 3.4.13.20, β-Ala-His dipeptidase.
[EC 3.4.13.3 created 1961 as EC 3.4.3.3, transferred 1972 to EC 3.4.13.3, modified 1989 (EC 3.4.13.13 created 1981, incorporated 1992), deleted 2011]
 
 
EC 3.4.13.4     
Accepted name: Xaa-Arg dipeptidase
Reaction: Preferential hydrolysis of Xaa┼Arg, Xaa┼Lys or Xaa┼ornithine dipeptides
Other name(s): aminoacyl-lysine dipeptidase; N2-(4-amino-butyryl)-L-lysine hydrolase; X-Arg dipeptidase
Comments: Widely distributed in mammals
References:
1.  Kumon, A., Matsuoka, Y., Kakimoto, Y., Nakajima, T. and Sano, I. A peptidase that hydrolyzes α-N-(γ-aminobutyryl)lysine. Biochim. Biophys. Acta 200 (1970) 466–474. [PMID: 5436646]
[EC 3.4.13.4 created 1972]
 
 
EC 3.4.13.5     
Accepted name: Xaa-methyl-His dipeptidase
Reaction: Hydrolysis of anserine (β-alanyl┼Nπ-methyl-L-histidine), carnosine, homocarnosine, glycyl┼leucine and other dipeptides with broad specificity
Other name(s): anserinase; aminoacyl-methylhistidine dipeptidase; acetylhistidine deacetylase; N-acetylhistidine deacetylase; α-N-acetyl-L-histidine aminohydrolase; X-methyl-His dipeptidase
References:
1.  Jones, N.R. The free amino acids of fish. 1-Methylhistidine and β-alanine liberation by skeletal muscle anserinase of codling (Gadus callarias). Biochem. J. 60 (1955) 81–87. [PMID: 14363188]
2.  Baslow, M.H. and Lenney, J.F. α-N-Acetyl-L-histidine amidohydrolase activity from the brain of the skipjack tuna Katsuwonus pelamis. Can. J. Biochem. 45 (1967) 337–340. [PMID: 6067033]
3.  Lenney, J.F., Baslow, M.H. and Sugiyama, G.H. Similarity of tuna N-acetylhistidine deacetylase and cod fish anserinase. Comp. Biochem. Physiol. B Comp. Biochem. 61 (1978) 253–258. [PMID: 318374]
[EC 3.4.13.5 created 1961 as EC 3.4.3.4, transferred 1972 to EC 3.4.13.5, modified 1981 (EC 3.5.1.34 created 1972, incorporated 1981)]
 
 
EC 3.4.13.6      
Transferred entry: Cys-Gly dipeptidase. Now EC 3.4.11.2, membrane alanyl aminopeptidase
[EC 3.4.13.6 created 1961 as EC 3.4.3.5, transferred 1972 to EC 3.4.13.6]
 
 
EC 3.4.13.7     
Accepted name: Glu-Glu dipeptidase
Reaction: Hydrolysis of the Glu┼Glu dipeptide
Other name(s): α-glutamyl-glutamate dipeptidase; glutamylglutamic arylamidase
Comments: It is unclear whether the specificity of this enzyme extends to other α-glutamyl dipeptides
References:
1.  Pratt, A.G., Crawford, E.J. and Friedkin, M. The hydrolysis of mono-, di-, and triglutamate derivatives of folic acid with bacterial enzymes. J. Biol. Chem. 243 (1968) 6367–6372. [PMID: 5726892]
[EC 3.4.13.7 created 1972]
 
 
EC 3.4.13.8      
Transferred entry: Pro-X dipeptidase. Now EC 3.4.13.18, cytosol nonspecific dipeptidase
[EC 3.4.13.8 created 1961 as EC 3.4.3.6, transferred 1972 to EC 3.4.13.8]
 
 
EC 3.4.13.9     
Accepted name: Xaa-Pro dipeptidase
Reaction: Hydrolysis of Xaa┼Pro dipeptides; also acts on aminoacyl-hydroxyproline analogs. No action on Pro-Pro
Other name(s): prolidase; imidodipeptidase; proline dipeptidase; peptidase D; γ-peptidase; X-Pro dipeptidase
Comments: A Mn2+-activated enzyme, in peptidase family M24 (methionyl aminopeptidase family); cytosolic from most animal tissues.
References:
1.  Davis, N.C. and Smith, E.L. Purification and some properties of prolidase of swine kidney. J. Biol. Chem. 224 (1957) 261–275. [PMID: 13398404]
2.  Sjöström, H., Norén, O. and Josefsson, L. Purification and specificity of pig intestinal prolidase. Biochim. Biophys. Acta 327 (1973) 457–470. [PMID: 4778946]
3.  Baksi, K. and Radhakrishnan, A.N. Purification and properties of prolidase (imidodipeptidase) from monkey small intestine. Indian J. Biochem. Biophys. 11 (1974) 7–11. [PMID: 4435812]
4.  Browne, P. and O'Cuinn, G. The purification and characterization of a proline dipeptidase from guinea pig brain. J. Biol. Chem. 258 (1983) 6147–6154. [PMID: 6853481]
[EC 3.4.13.9 created 1961 as EC 3.4.3.7, transferred 1972 to EC 3.4.13.9]
 
 
EC 3.4.13.10      
Transferred entry: β-aspartyldipeptidase. Now EC 3.4.19.5, β-aspartyl-peptidase
[EC 3.4.13.10 created 1972, deleted 1992]
 
 
EC 3.4.13.11      
Transferred entry: dipeptidase. Now EC 3.4.13.19, membrane dipeptidase
[EC 3.4.13.11 created 1972, deleted 1992]
 
 
EC 3.4.13.12     
Accepted name: Met-Xaa dipeptidase
Reaction: Hydrolysis of Met┼Xaa dipeptides
Other name(s): methionyl dipeptidase; dipeptidase M; Met-X dipeptidase
Comments: A Mn2+-activated Escherichia coli enzyme with thiol dependence
References:
1.  Brown, J.L. Purification and properties of dipeptidase M from Escherichia coli B. J. Biol. Chem. 248 (1973) 409–416. [PMID: 4567782]
[EC 3.4.13.12 created 1976]
 
 
EC 3.4.13.13      
Transferred entry: homocarnosinase. Now EC 3.4.13.3, X-His dipeptidase
[EC 3.4.13.13 created 1981, deleted 1992]
 
 
EC 3.4.13.14      
Deleted entry:  γ-glutamyldipeptidase
[EC 3.4.13.14 created 1989, deleted 1992]
 
 
EC 3.4.13.15      
Transferred entry: N2-β-alanylarginine dipeptidase. Now EC 3.4.13.18, cytosol nonspecific dipeptidase
[EC 3.4.13.15 created 1989, deleted 1992]
 
 
EC 3.4.13.16      
Deleted entry:  aspartylphenylalanine dipeptidase
[EC 3.4.13.16 created 1989, deleted 1992]
 
 
EC 3.4.13.17     
Accepted name: non-stereospecific dipeptidase
Reaction: Hydrolysis of dipeptides containing either D- or L-amino acids or both
Other name(s): peptidyl-D-amino acid hydrolase; D-(or L-)aminoacyl-dipeptidase
Comments: A digestive enzyme of cephalopods
References:
1.  D'Aniello, A. and Strazullo, L. Peptidyl-D-amino acid hydrolase from Loligo vulgaris Lam. J. Biol. Chem. 259 (1984) 4237–4243. [PMID: 6444201]
[EC 3.4.13.17 created 1990]
 
 
EC 3.4.13.18     
Accepted name: cytosol nonspecific dipeptidase
Reaction: Hydrolysis of dipeptides, preferentially hydrophobic dipeptides including prolyl amino acids
Other name(s): N2-β-alanylarginine dipeptidase; glycyl-glycine dipeptidase; glycyl-leucine dipeptidase; iminodipeptidase; peptidase A; Pro-X dipeptidase; prolinase; prolyl dipeptidase; prolylglycine dipeptidase; iminodipeptidase; prolinase; L-prolylglycine dipeptidase; prolylglycine dipeptidase; diglycinase; Gly-Leu hydrolase; glycyl-L-leucine dipeptidase; glycyl-L-leucine hydrolase; glycyl-L-leucine peptidase; L-amino-acyl-L-amino-acid hydrolase; glycylleucine peptidase; glycylleucine hydrolase; glycylleucine dipeptide hydrolase; non-specific dipeptidase; human cytosolic non-specific dipeptidase; glycyl-L-leucine hydrolase; glycyl-glycine dipeptidase
Comments: A zinc enzyme with broad specificity, varying somewhat with source species. Activated and stabilized by dithiothreitol and Mn2+. Inhibited by bestatin and leucine.
References:
1.  Bauer, K. Cytosol non-specific dipeptidase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 1520–1522.
[EC 3.4.13.18 created 1961 as EC 3.4.3.1 and EC 3.4.3.2, transferred 1972 to EC 3.4.13.1 and EC 3.4.13.2, transferred 1978 to EC 3.4.13.11, part transferred 1992 to EC 3.4.13.18, modified 2000 (EC 3.4.13.15 created 1989, incorporated 1992)]
 
 
EC 3.4.13.19     
Accepted name: membrane dipeptidase
Reaction: Hydrolysis of dipeptides
Other name(s): renal dipeptidase; dehydropeptidase I (DPH I); dipeptidase (ambiguous); aminodipeptidase; dipeptide hydrolase (ambiguous); dipeptidyl hydrolase (ambiguous); nonspecific dipeptidase; glycosyl-phosphatidylinositol-anchored renal dipeptidase; MDP
Comments: A membrane-bound, zinc enzyme with broad specificity. Abundant in the kidney cortex. Inhibited by bestatin and cilastatin. Type example of peptidase family M19.
References:
1.  Campbell, B., Lin, H., Davis, R. and Ballew, E. The purification and properties of a particulate renal dipeptidase. Biochim. Biophys. Acta 118 (1966) 371–386. [PMID: 5961612]
2.  Campbell, B.J. Renal dipeptidase. Methods Enzymol. 19 (1970) 722–729.
3.  Kropp, H., Sundelof, J.G., Hajdu, R. and Kahan, F.M. Metabolism of thienamycin and related carbapenem antibiotics by renal dipeptidase, dehydropeptidase-I. Antimicrob. Agents Chemother. 22 (1982) 62–70. [PMID: 7125632]
4.  Hooper, N.M., Keen, J.N. and Turner, A.J. Characterization of the glycosyl-phosphatidylinositol-anchored human renal dipeptidase reveals that it is more extensively glycosylated than the pig enzyme. Biochem. J. 265 (1990) 429–433. [PMID: 2137335]
[EC 3.4.13.19 created 1961 as EC 3.4.3.1 and EC 3.4.3.2, transferred 1972 to EC 3.4.13.1 and EC 3.4.13.2, transferred 1978 to EC 3.4.13.11, part transferred 1992 to EC 3.4.13.19, modified 2011]
 
 
EC 3.4.13.20     
Accepted name: β-Ala-His dipeptidase
Reaction: Preferential hydrolysis of the β-Ala┼His dipeptide (carnosine), and also anserine, Xaa┼His dipeptides and other dipeptides including homocarnosine
Other name(s): serum carnosinase
Comments: Present in the serum of humans and higher primates, but not in the serum of other mammals. Activated by Cd2+ and citrate. Belongs in peptidase family M20.
References:
1.  Lenney, J.F., George, R.P., Weiss, A.M., Kucera, C.M., Chan, P.W.H. and Rinzler, G.S. Human serum carnosinase: characterization, distinction from cellular carnosinase, and activation by cadmium. Clin. Chim. Acta 123 (1982) 221–231. [PMID: 7116644]
2.  Jackson, M.C., Kucera, C.M. and Lenney, J.F. Purification and properties of human serum carnosinase. Clin. Chim. Acta 196 (1991) 193–206. [PMID: 1903095]
[EC 3.4.13.20 created 1992]
 
 
EC 3.4.13.21     
Accepted name: dipeptidase E
Reaction: Dipeptidase E catalyses the hydrolysis of dipeptides Asp┼Xaa. It does not act on peptides with N-terminal Glu, Asn or Gln, nor does it cleave isoaspartyl peptides
Other name(s): aspartyl dipeptidase; peptidase E; PepE gene product (Salmonella typhimurium)
Comments: A free carboxy group is not absolutely required in the substrate since Asp-Phe-NH2 and Asp-Phe-OMe are hydrolysed somewhat more slowly than dipeptides with free C-termini. No peptide larger than a C-blocked dipeptide is known to be a substrate. Asp-NH-Np is hydrolysed and is a convenient substrate for routine assay. The enzyme is most active near pH 7.0, and is not inhibited by di-isopropylfluorophosphate or phenylmethanesulfonyl fluoride. Belongs in peptidase family S51.
References:
1.  Haakansson, K., Wang, A.H.J. and Miller, C.G. The structure of aspartyl dipeptidase reveals a unique fold with a Ser-His-Glu catalytic triad. Proc. Natl. Acad. Sci. USA 97 (2000) 14097–14102. [PMID: 11106384]
2.  Lassy, R.A.L. and Miller, C.G. Peptidase E, a peptidase specific for N-terminal aspartic dipeptides, is a serine hydrolase. J. Bacteriol. 182 (2000) 2536–2543. [PMID: 10762256]
[EC 3.4.13.21 created 2001]
 
 
EC 3.4.13.22     
Accepted name: D-Ala-D-Ala dipeptidase
Reaction: D-Ala-D-Ala + H2O = 2 D-Ala
Other name(s): D-alanyl-D-alanine dipeptidase; vanX D-Ala-D-Ala dipeptidase; VanX
Comments: A Zn2+-dependent enzyme [4]. The enzyme protects Enterococcus faecium from the antibiotic vancomycin, which can bind to the -D-Ala-D-Ala sequence at the C-terminus of the peptidoglycan pentapeptide (see diagram). This enzyme reduces the availability of the free dipeptide D-Ala-D-Ala, which is the precursor for this pentapeptide sequence, allowing D-Ala-(R)-lactate (for which vancomycin has much less affinity) to be added to the cell wall instead [2,3]. The enzyme is stereospecific, as L-Ala-L-Ala, D-Ala-L-Ala and L-Ala-D-Ala are not substrates [2]. Belongs in peptidase family M15.
References:
1.  Reynolds, P.E., Depardieu, F., Dutka-Malen, S., Arthur, M. and Courvalin, P. Glycopeptide resistance mediated by enterococcal transposon Tn1546 requires production of VanX for hydrolysis of D-alanyl-D-alanine. Mol. Microbiol. 13 (1994) 1065–1070. [PMID: 7854121]
2.  Wu, Z., Wright, G.D. and Walsh, C.T. Overexpression, purification, and characterization of VanX, a D-, D-dipeptidase which is essential for vancomycin resistance in Enterococcus faecium BM4147. Biochemistry 34 (1995) 2455–2463. [PMID: 7873524]
3.  McCafferty, D.G., Lessard, I.A. and Walsh, C.T. Mutational analysis of potential zinc-binding residues in the active site of the enterococcal D-Ala-D-Ala dipeptidase VanX. Biochemistry 36 (1997) 10498–10505. [PMID: 9265630]
4.  Bussiere, D.E., Pratt, S.D., Katz, L., Severin, J.M., Holzman, T. and Park, C.H. The structure of VanX reveals a novel amino-dipeptidase involved in mediating transposon-based vancomycin resistance. Mol. Cell. 2 (1998) 75–84. [PMID: 9702193]
5.  Tan, A.L., Loke, P. and Sim, T.S. Molecular cloning and functional characterisation of VanX, a D-alanyl-D-alanine dipeptidase from Streptomyces coelicolor A3(2). Res. Microbiol. 153 (2002) 27–32. [PMID: 11881895]
6.  Matthews, M.L., Periyannan, G., Hajdin, C., Sidgel, T.K., Bennett, B. and Crowder, M.W. Probing the reaction mechanism of the D-ala-D-ala dipeptidase, VanX, by using stopped-flow kinetic and rapid-freeze quench EPR studies on the Co(II)-substituted enzyme. J. Am. Chem. Soc. 128 (2006) 13050–13051. [PMID: 17017774]
[EC 3.4.13.22 created 2006]
 
 
EC 3.4.14.1     
Accepted name: dipeptidyl-peptidase I
Reaction: Release of an N-terminal dipeptide, Xaa-Yaa┼Zaa-, except when Xaa is Arg or Lys, or Yaa or Zaa is Pro
Other name(s): cathepsin C; dipeptidyl aminopeptidase I; dipeptidyl transferase; cathepsin C; dipeptidyl transferase; dipeptide arylamidase I; DAP I
Comments: A Cl--dependent, lysosomal cysteine-type peptidase maximally active at acidic pH. Also polymerizes dipeptide amides, arylamides and esters at neutral pH. In peptidase family C1 (papain family).
References:
1.  Planta, R.J., Gorter, J. and Gruber, M. The catalytic properties of cathepsin C. Biochim. Biophys. Acta 89 (1964) 511–519. [PMID: 14209333]
2.  Metrione, R.M., Neves, A.G. and Fruton, J.S. Purification and properties of dipeptidyl transferase (cathepsin C). Biochemistry 5 (1966) 1597–1604. [PMID: 5961281]
3.  McDonald, J.K., Zeitman, B.B., Reilly, T.J. and Ellis, S. New observations on the substrate specificity of cathepsin C (dipeptidyl aminopeptidase I) including the degradation of β-corticotropin and other peptide hormones. J. Biol. Chem. 244 (1969) 2693–2709. [PMID: 4306035]
4.  McDonald, J.K. and Schwabe, C. Intracellular exopeptidases. In: Barrett, A.J. (Ed.), Proteinases in Mammalian Cells and Tissues, North-Holland Publishing Co., Amsterdam, 1977, pp. 311–391.
[EC 3.4.14.1 created 1961 as EC 3.4.4.9, transferred 1972 to EC 3.4.14.1]
 
 
EC 3.4.14.2     
Accepted name: dipeptidyl-peptidase II
Reaction: Release of an N-terminal dipeptide, Xaa-Yaa┼, preferentially when Yaa is Ala or Pro. Substrates are oligopeptides, preferentially tripeptides
Other name(s): dipeptidyl aminopeptidase II; dipeptidyl arylamidase II; carboxytripeptidase; dipeptidyl peptidase II; dipeptidyl arylamidase II; DAP II; dipeptidyl(amino)peptidase II; dipeptidylarylamidase
Comments: A lysosomal serine-type peptidase in family S28 (Pro-X carboxypeptidase family); maximally active at acidic pH
References:
1.  McDonald, J.K., Reilly, T.J., Zeitman, B.B. and Ellis, S. Dipeptidyl arylamidase II of the pituitary. Properties of lysyl-alanyl-β-naphthylamide hydrolysis: inhibition by cations, distribution in tissues and subcellular localization. J. Biol. Chem. 243 (1968) 4143–4150. [PMID: 4969969]
2.  McDonald, J.K. and Schwabe, C. Intracellular exopeptidases. In: Barrett, A.J. (Ed.), Proteinases in Mammalian Cells and Tissues, North-Holland Publishing Co., Amsterdam, 1977, pp. 311–391.
[EC 3.4.14.2 created 1978]
 
 
EC 3.4.14.3      
Transferred entry: acylamino-acid-releasing enzyme. Now EC 3.4.19.1, acylaminoacyl-peptidase
[EC 3.4.14.3 created 1978, deleted 1981]
 
 
EC 3.4.14.4     
Accepted name: dipeptidyl-peptidase III
Reaction: Release of an N-terminal dipeptide from a peptide comprising four or more residues, with broad specificity. Also acts on dipeptidyl 2-naphthylamides.
Other name(s): dipeptidyl aminopeptidase III; dipeptidyl arylamidase III; enkephalinase B; red cell angiotensinase
Comments: A cytosolic peptidase that is active at neutral pH. It has broad activity on peptides, although it is highly selective for Arg-Arg-2-naphthylamide, at pH 9.2. Active in the hydrolysis of enkephalins. A metallopeptidase, the type example of peptidase family M49.
References:
1.  McDonald, J.K. Dipeptidyl-peptidase III. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 536–538.
2.  Fukasawa, K., Fukasawa, K.M., Iwamoto, H., Hirose, J. and Harada, M. The HELLGH motif of rat liver dipeptidyl peptidase III is involved in zinc coordination and the catalytic activity of the enzyme. Biochemistry 38 (1999) 8299–8303. [PMID: 10387075]
[EC 3.4.14.4 created 1981, modified 2001]
 
 
EC 3.4.14.5     
Accepted name: dipeptidyl-peptidase IV
Reaction: Release of an N-terminal dipeptide, Xaa-Yaa┼Zaa-, from a polypeptide, preferentially when Yaa is Pro, provided Zaa is neither Pro nor hydroxyproline
Other name(s): dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GP110; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycylprolyl dipeptidylaminopeptidase; dipeptidyl-peptide hydrolase; glycylprolyl aminopeptidase; dipeptidyl-aminopeptidase IV; DPP IV/CD26; amino acyl-prolyl dipeptidyl aminopeptidase; T cell triggering molecule Tp103; X-PDAP
Comments: A homodimer. An integral protein of the plasma membrane of lymphocytes and other mammalian cells, in peptidase family S9 (prolyl oligopeptidase family). The reaction is similar to that of the unrelated EC 3.4.14.11 Xaa-Pro dipeptidyl-peptidase of lactococci
References:
1.  Misumi, Y., Hayashi, Y., Arakawa, F. and Ikehara, Y. Molecular cloning and sequence analysis of human dipeptidyl peptidase IV, a serine proteinase on the cell surface. Biochim. Biophys. Acta 1131 (1992) 333–336. [PMID: 1352704]
2.  David, F., Bernard, A.-M., Pierres, M. and Marguet, D. Identification of serine 624, aspartic acid 702, and histidine 734 as the catalytic triad residues of mouse dipeptidyl-peptidase IV (CD26). A member of a novel family of nonclassical serine hydrolases. J. Biol. Chem. 268 (1993) 17247–17252. [PMID: 8102366]
3.  Ikehara, Y., Ogata, S. and Misumi, Y. Dipeptidyl-peptidase IV from rat liver. Methods Enzymol. 244 (1994) 215–227. [PMID: 7845210]
[EC 3.4.14.5 created 1981, modified 1996]
 
 
EC 3.4.14.6     
Accepted name: dipeptidyl-dipeptidase
Reaction: Preferential release of dipeptides from a tetrapeptide, e.g. Ala-Gly┼Ala-Gly. Acts more slowly on Ala-Ala┼Ala-Ala and Gly-Gly┼Gly-Gly
Other name(s): dipeptidyl tetrapeptide hydrolase; dipeptidyl ligase; tetrapeptide dipeptidase
Comments: A thiol-activated peptidase from cabbage (Brassica oleracea). Tetrapeptides are formed from Ala-Ala, Gly-Gly, Ala-Gly and Gly-Ala
References:
1.  Eng, F.W.H.T. Dipeptidyl tetrapeptide hydrolase, a new enzyme with dipeptidyl ligase activity. Can. J. Biochem. Cell. Biol. 62 (1984) 516–528.
[EC 3.4.14.6 created 1989]
 
 
EC 3.4.14.7      
Deleted entry:  tetralysine endopeptidase
[EC 3.4.14.7 created 1989, deleted 1992]
 
 
EC 3.4.14.8      
Transferred entry: tripeptidyl peptidase. Now EC 3.4.14.10, tripeptidyl-peptidase II
[EC 3.4.14.8 created 1989, deleted 1992]
 
 
EC 3.4.14.9     
Accepted name: tripeptidyl-peptidase I
Reaction: Release of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity.
Other name(s): tripeptidyl aminopeptidase; tripeptidyl peptidase
Comments: A lysosomal enzyme that is active at acidic pH. Deficient in classical late-infantile neuronal ceroid lipofuscinosis brain tissue. Belongs in peptidase family S53. Formerly included in EC 3.4.14.8.
References:
1.  Ezaki, J., Tanida, I., Kanehagi, N. and Kominami, E. A lysosomal proteinase, the late infantile neuronal ceroid lipofuscinosis gene (CLN2) product, is essential for degradation of a hydrophobic protein, the subunit c of ATP synthase. J. Neurochem. 72 (1999) 2573–2582. [PMID: 10349869]
2.  Rawlings, N.D. and Barrett, A.J. Tripeptidyl-peptidase I is apparently the CLN2 protein absent in classical late-infantile neuronal ceroid lipofuscinosis. Biochim. Biophys. Acta 1429 (1999) 496–500. [PMID: 9989235]
3.  Ezaki, J., Takeda-Ezaki, M., Oda, K. and Kominami, E. Characterization of endopeptidase activity of tripeptidyl peptidase-I/CLN2 protein which is deficient in classical late infantile neuronal ceroid lipofuscinosis. Biochem. Biophys. Res. Commun. 268 (2000) 904–908. [PMID: 10679303]
4.  Junaid, M.A., Wu, G.X. and Pullarkat, R.K. Purification and characterization of bovine brain lysosomal pepstatin-insensitive proteinase, the gene product deficient in the human late-infantile neuronal ceroid lipofuscinosis. J. Neurochem. 74 (2000) 287–294. [PMID: 10617131]
5.  Lin, L., Sohar, I., Lackland, H. and Lobel, P. The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH. J. Biol. Chem. 276 (2001) 2249–2255. [PMID: 11054422]
[EC 3.4.14.9 created 1992 (part of EC 3.4.14.8 created 1989, incorporated 1992), modified 2000, modified 2001, modified 2003]
 
 
EC 3.4.14.10     
Accepted name: tripeptidyl-peptidase II
Reaction: Release of an N-terminal tripeptide from a polypeptide
Other name(s): tripeptidyl aminopeptidase; tripeptidyl peptidase; tripeptidyl aminopeptidase II; tripeptidyl peptidase II; TPP
Comments: A cytosolic enzyme in peptidase family S8 (subtilisin family). Active at neutral pH. Inhibited by diisopropyl fluorophosphate. Formerly included in EC 3.4.14.8
References:
1.  Bålöw, R.M., Ragnarsson, U. and Zetterqvist, Ö. Tripeptidyl aminopeptidase in the extralysosomal fraction of rat liver. J. Biol. Chem. 258 (1983) 11622–11628. [PMID: 6352701]
2.  Bålöw, R.M., Tomkinson, B., Ragnarsson, U. and Zetterqvist, Ö. Purification, substrate specificity, and classification of tripeptidyl peptidase II. J. Biol. Chem. 261 (1986) 2409–2417. [PMID: 3511062]
3.  Tomkinson, B. and Zetterqvist, Ö. Immunological cross-reactivity between human tripeptidyl peptidase II and fibronectin. Biochem. J. 267 (1990) 149–154. [PMID: 1691635]
[EC 3.4.14.10 created 1992 (part of EC 3.4.14.8 created 1989, incorporated 1992)]
 
 
EC 3.4.14.11     
Accepted name: Xaa-Pro dipeptidyl-peptidase
Reaction: Hydrolyses Xaa-Pro┼ bonds to release unblocked, N-terminal dipeptides from substrates including Ala-Pro┼p-nitroanilide and (sequentially) Tyr-Pro┼Phe-Pro┼Gly-Pro┼Ile
Other name(s): X-prolyl dipeptidyl aminopeptidase; PepX; X-prolyl dipeptidyl peptidase; X-Pro dipeptidyl-peptidase
Comments: The intracellular enzyme from Lactococcus lactis (190-kDa) is the type example of peptidase family S15. The reaction is similar to that catalysed by dipeptidyl-peptidase IV of animals
References:
1.  Zevaco, C., Monnet, V. and Gripon, J.-C. Intracellular X-prolyl dipeptidyl peptidase from Lactococcus lactis spp. lactis: purification and properties. J. Appl. Bacteriol. 68 (1990) 357–366.
2.  Meyer-Barton, E.C., Klein, J.R., Imam, M. and Plapp, R. Cloning and sequence analysis of the X-prolyl-dipeptidyl-aminopeptidase gene (pepX) from Lactobacillus delbrückii ssp. lactis DSM7290. Appl. Microbiol. Biotechnol. 40 (1993) 82–89. [PMID: 7765315]
3.  Habibi-Najafi, M.B. and Lee, B.H. Purification and characterization of X-prolyl dipeptidyl peptidase from Lactobacillus casei subsp. casei LLG. Appl. Microbiol. Biotechnol. 42 (1994) 280–286. [PMID: 7765768]
4.  Chich, J.-F., Gripon, J.-C. and Ribadeau-Dumas, B. Preparation of bacterial X-prolyl dipeptidyl aminopeptidase and its stabilization by organic cosolvents. Anal. Biochem. 224 (1995) 245–249. [PMID: 7710078]
5.  Chich, J.-F., Chapot-Chartier, M.P., Ribadeau-Dumas, B. and Gripon, J.-C. Identification of the active site serine of the X-prolyl aminopeptidase from Lactococcus lactis. FEBS Lett. 314 (1995) 139–142.
[EC 3.4.14.11 created 1996]
 
 
EC 3.4.14.12     
Accepted name: Xaa-Xaa-Pro tripeptidyl-peptidase
Reaction: Hydrolysis of Xaa-Xaa-Pro┼Yaa- releasing the N-terminal tripeptide of a peptide with Pro as the third residue (position P1) and where Yaa is not proline
Other name(s): prolyltripeptidyl amino peptidase; prolyl tripeptidyl peptidase; prolyltripeptidyl aminopeptidase; PTP-A; TPP
Comments: This cell-surface-associated serine exopeptidase is found in the Gram-negative, anaerobic bacterium Porphyromonas gingivalis, which has been implicated in adult periodontal disease [1]. The enzyme releases the N-terminal tripeptide of peptides, such as interleukin-6. It has an absolute requirement for a proline residue at the P1 position but is completely inactivated by a proline residue at the P1′ position [1]. The size of the peptide does not affect the rate of reaction [1].
References:
1.  Banbula, A., Mak, P., Bugno, M., Silberring, J., Dubin, A., Nelson, D., Travis, J. and Potempa, J. Prolyl tripeptidyl peptidase from Porphyromonas gingivalis. A novel enzyme with possible pathological implications for the development of periodontitis. J. Biol. Chem. 274 (1999) 9246–9252. [PMID: 10092598]
2.  Fujimura, S., Ueda, O., Shibata, Y. and Hirai, K. Isolation and properties of a tripeptidyl peptidase from a periodontal pathogen Prevotella nigrescens. FEMS Microbiol. Lett. 219 (2003) 305–309. [PMID: 12620636]
[EC 3.4.14.12 created 2006]
 
 
EC 3.4.14.13     
Accepted name: γ-D-glutamyl-L-lysine dipeptidyl-peptidase
Reaction: The enzyme releases L-Ala-γ-D-Glu dipeptides from cell wall peptides via cleavage of an L-Ala-γ-D-Glu┼L-Lys bond.
Other name(s): YkfC
Comments: The enzyme, characterized from the bacterium Bacillus subtilis, is involved in the recycling of the murein peptide.
References:
1.  Schmidt, D.M., Hubbard, B.K. and Gerlt, J.A. Evolution of enzymatic activities in the enolase superfamily: functional assignment of unknown proteins in Bacillus subtilis and Escherichia coli as L-Ala-D/L-Glu epimerases. Biochemistry 40 (2001) 15707–15715. [PMID: 11747447]
2.  Xu, Q., Abdubek, P., Astakhova, T., Axelrod, H.L., Bakolitsa, C., Cai, X., Carlton, D., Chen, C., Chiu, H.J., Chiu, M., Clayton, T., Das, D., Deller, M.C., Duan, L., Ellrott, K., Farr, C.L., Feuerhelm, J., Grant, J.C., Grzechnik, A., Han, G.W., Jaroszewski, L., Jin, K.K., Klock, H.E., Knuth, M.W., Kozbial, P., Krishna, S.S., Kumar, A., Lam, W.W., Marciano, D., Miller, M.D., Morse, A.T., Nigoghossian, E., Nopakun, A., Okach, L., Puckett, C., Reyes, R., Tien, H.J., Trame, C.B., van den Bedem, H., Weekes, D., Wooten, T., Yeh, A., Hodgson, K.O., Wooley, J., Elsliger, M.A., Deacon, A.M., Godzik, A., Lesley, S.A. and Wilson, I.A. Structure of the γ-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66 (2010) 1354–1364. [PMID: 20944232]
[EC 3.4.14.13 created 2015]
 
 
EC 3.4.15.1     
Accepted name: peptidyl-dipeptidase A
Reaction: Release of a C-terminal dipeptide, oligopeptide┼Xaa-Yaa, when Xaa is not Pro, and Yaa is neither Asp nor Glu. Thus, conversion of angiotensin I to angiotensin II, with increase in vasoconstrictor activity, but no action on angiotensin II
Glossary: captopril = (2S)-1-(3-mercapto-2-methylpropanoyl)-L-proline
Other name(s): dipeptidyl carboxypeptidase I; peptidase P; dipeptide hydrolase (ambiguous); peptidyl dipeptidase; angiotensin converting enzyme; kininase II; angiotensin I-converting enzyme; carboxycathepsin; dipeptidyl carboxypeptidase; peptidyl dipeptidase I; peptidyl-dipeptide hydrolase; peptidyldipeptide hydrolase; endothelial cell peptidyl dipeptidase; ACE; peptidyl dipeptidase-4; PDH; peptidyl dipeptide hydrolase; DCP
Comments: A Cl--dependent, zinc glycoprotein that is generally membrane-bound. A potent inhibitor is captopril. Important in elevation of blood pressure, through formation of angiotensin II (vasoconstrictor) and destruction of bradykinin (vasodilator). Two molecular forms exist in mammalian tissues, a widely-distributed somatic form of 150- to 180-kDa that contains two non-identical catalytic sites, and a testicular form of 90- to 100-kDa that contains only a single catalytic site. Type example of peptidase family M2
References:
1.  Soubrier, F., Alhenc-Gelas, F., Hubert, C., Allegrini, J., John, M., Tregear, G. and Corvol, P. Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc. Natl. Acad. Sci. USA 85 (1988) 9386–9390. [PMID: 2849100]
2.  Ehlers, M.R.W., Fox, E.A., Strydom, D.J. and Riordan, J.F. Molecular cloning of human testicular angiotensin-converting enzyme: the testis enzyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc. Natl. Acad. Sci. USA 86 (1989) 7741–7745. [PMID: 2554286]
3.  Wei, L., Clauser, E., Alhenc-Gelas, F. and Corvol, P. The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors. J. Biol. Chem. 267 (1992) 13398–13405. [PMID: 1320019]
4.  Corvol, P., Williams, T.A. and Soubrier, F. Peptidyl dipeptidase A: angiotensin I-converting enzyme. Methods Enzymol. 248 (1995) 283–305. [PMID: 7674927]
[EC 3.4.15.1 created 1972, modified 1981, modified 1989, modified 1996, modified 2011]
 
 
EC 3.4.15.2      
Transferred entry: pepdidyl carboxyamidase. Now EC 3.4.19.2, peptidyl-glycinamidase
[EC 3.4.15.2 created 1978, deleted 1981]
 
 
EC 3.4.15.3      
Transferred entry: dipeptidyl carboxypeptidase. Now EC 3.4.15.5, peptidyl-dipeptidase Dcp
[EC 3.4.15.3 created 1981, modified 1989, deleted 1996]
 
 
EC 3.4.15.4     
Accepted name: peptidyl-dipeptidase B
Reaction: Release of a C-terminal dipeptide or exceptionally a tripeptide
Other name(s): dipeptidyl carboxyhydrolase; atriopeptin convertase; atrial di-(tri)peptidyl carboxyhydrolase; peptidyldipeptidase B; atrial dipeptidyl carboxyhydrolase; atrial peptide convertase
Comments: A membrane-bound, zinc metallopeptidase located in mammalian atrial, but not ventricular, myocytes. Although it is capable of converting the 126-residue atriopeptin III directly to atriopeptin I by releasing a C-terminal tripeptide Phe-Arg-Tyr, it is generally restricted to the release of dipeptides. In contrast to peptidyl-dipeptidase A (EC 3.4.15.1) it displays no Cl- dependence and shows no action on angiotensin I. Conversely, peptidyl-dipeptidase A is unable to release Phe-Arg from the C-terminus of atriopeptin II
References:
1.  Harris, R.B. and Wilson, I.B. Atrial tissue contains a metallo dipeptidyl carboxyhydrolase not present in ventricular tissue: partial purification and characterization. Arch. Biochem. Biophys. 233 (1984) 667–675. [PMID: 6385859]
2.  Harris, R.B. and Wilson, I.B. Conversion of atriopeptin II to atriopeptin I by atrial dipeptidyl carboxy hydrolase. Peptides (Fayetteville) 6 (1985) 393–396. [PMID: 2999723]
3.  Soler, D.F. and Harris, R.B. Continuous fluorogenic substrates for atrial dipeptidyl carboxyhydrolase. Importance of Ser in the P1 position. Int. J. Peptide Protein Res. 32 (1988) 35–40. [PMID: 3146555]
4.  Soler, D.F. and Harris, R.B. Atrial dipeptidyl carboxyhydrolase is a zinc-metallo proteinase which possesses tripeptidyl carboxyhydrolase activity. Peptides (Fayetteville) 10 (1989) 63–68. [PMID: 2501770]
[EC 3.4.15.4 created 1992]
 
 
EC 3.4.15.5     
Accepted name: peptidyl-dipeptidase Dcp
Reaction: Hydrolysis of unblocked, C-terminal dipeptides from oligopeptides, with broad specificity. Does not hydrolyse bonds in which P1′ is Pro, or both P1 and P1′ are Gly
Other name(s): dipeptidyl carboxypeptidase (Dcp); dipeptidyl carboxypeptidase
Comments: Known from Escherichia coli and Salmonella typhimurium. A zinc metallopeptidase in peptidase family M3 (thimet oligopeptidase family). Ac-Ala┼Ala-Ala is a good test substrate [3]. Inhibited by captopril, as is peptidyl-dipeptidase A. Formerly EC 3.4.15.3, and included in EC 3.4.15.1, peptidyl-dipeptidase A.
References:
1.  Yaron, A. Dipeptidyl carboxypeptidase from Escherichia coli. Methods Enzymol. 45 (1976) 599–610. [PMID: 13271]
2.  Henrich, B., Becker, S., Schroeder, U. and Plapp, R. dcp gene of Escherichia coli: cloning, sequencing, transcript mapping, and characterization of the gene product. J. Bacteriol. 175 (1993) 7290–7300. [PMID: 8226676]
3.  Conlin, C.A. and Miller, C.G. Oligopeptidase A and peptidyl-dipeptidase of Escherichia and Salmonella. Methods Enzymol. 248 (1995) 567–579. [PMID: 7674945]
[EC 3.4.15.5 created 1981 as EC 3.4.15.3, modified 1989, transferred 1996 to EC 3.4.15.5]
 
 
EC 3.4.15.6     
Accepted name: cyanophycinase
Reaction: [L-Asp(4-L-Arg)]n + H2O = [L-Asp(4-L-Arg)]n-1 + L-Asp(4-L-Arg)
Glossary: cyanophycin = [L-Asp(4-L-Arg)]n = N-β-aspartylarginine = [L-4-(L-arginin-2-N-yl)aspartic acid]n = poly{N4-[(1S)-1-carboxy-4-guanidinobutyl]-L-asparagine}
Other name(s): cyanophycin degrading enzyme; β-Asp-Arg hydrolysing enzyme; CGPase; CphB; CphE; cyanophycin granule polypeptidase; extracellular CGPase
Comments: The enzyme is highly specific for the branched polypeptide cyanophycin and does not hydrolyse poly-L-aspartate or poly-L-arginine [3]. A serine-type exopeptidase that belongs in peptidase family S51.
References:
1.  Obst, M., Krug, A., Luftmann, H. and Steinbüchel, A. Degradation of cyanophycin by Sedimentibacter hongkongensis strain KI and Citrobacter amalonaticus strain G isolated from an anaerobic bacterial consortium. Appl. Environ. Microbiol. 71 (2005) 3642–3652. [PMID: 16000772]
2.  Obst, M., Oppermann-Sanio, F.B., Luftmann, H. and Steinbüchel, A. Isolation of cyanophycin-degrading bacteria, cloning and characterization of an extracellular cyanophycinase gene (cphE) from Pseudomonas anguilliseptica strain BI. The cphE gene from P. anguilliseptica BI encodes a cyanophycin-hydrolyzing enzyme. J. Biol. Chem. 277 (2002) 25096–25105. [PMID: 11986309]
3.  Richter, R., Hejazi, M., Kraft, R., Ziegler, K. and Lockau, W. Cyanophycinase, a peptidase degrading the cyanobacterial reserve material multi-L-arginyl-poly-L-aspartic acid (cyanophycin): molecular cloning of the gene of Synechocystis sp. PCC 6803, expression in Escherichia coli, and biochemical characterization of the purified enzyme. Eur. J. Biochem. 263 (1999) 163–169. [PMID: 10429200]
[EC 3.4.15.6 created 2007]
 
 
EC 3.4.16.1      
Transferred entry: serine carboxypeptidase. Now EC 3.4.16.6, carboxypeptidase D
[EC 3.4.16.1 created 1972 as EC 3.4.12.1 and EC 3.4.21.13, both transferred 1978 to EC 3.4.16.1, deleted 1993]
 
 
EC 3.4.16.2     
Accepted name: lysosomal Pro-Xaa carboxypeptidase
Reaction: Cleavage of a -Pro┼Xaa bond to release a C-terminal amino acid
Other name(s): angiotensinase C; lysosomal carboxypeptidase C; peptidylprolylamino acid carboxypeptidase; aminoacylproline carboxypeptidase; prolyl carboxypeptidase; carboxypeptidase P; proline-specific carboxypeptidase P; PCP; lysosomal Pro-Xaa carboxypeptidase
Comments: A lysosomal peptidase active at acidic pH that inactivates angiotensin II. Inhibited by diisopropyl fluorophosphate. In peptidase family S28 (Pro-X carboxypeptidase family).
References:
1.  Walter, R., Simmons, W.H. and Yoshimoto, T. Proline specific endo- and exopeptidases. Mol. Cell. Biochem. 30 (1980) 111–127. [PMID: 6991912]
2.  Odya, C.E. and Erdös, E.G. Human prolylcarboxypeptidase. Methods Enzymol. 80 (1981) 460–466. [PMID: 7341916]
[EC 3.4.16.2 created 1972 as EC 3.4.12.4, transferred 1978 to EC 3.4.16.2]
 
 
EC 3.4.16.3      
Transferred entry: tyrosine carboxypeptidase. Now included with EC 3.4.16.5, carboxypeptidase C
[EC 3.4.16.3 created 1972 as EC 3.4.12.12, transferred 1978 to EC 3.4.16.3, deleted 1992]
 
 
EC 3.4.16.4     
Accepted name: serine-type D-Ala-D-Ala carboxypeptidase
Reaction: Preferential cleavage: (Ac)2-L-Lys-D-Ala┼D-Ala. Also transpeptidation of peptidyl-alanyl moieties that are N-acyl substituents of D-alanine
Other name(s): DD-peptidase; D-alanyl-D-alanine-carboxypeptidase; D-alanyl-D-alanine-cleaving-peptidase; D-alanyl-D-alanine-cleaving peptidase; DD-transpeptidase; D-alanine carboxypeptidase; DD-carboxypeptidase; D-alanyl carboxypeptidase
Comments: A membrane-bound, bacterial enzyme inhibited by penicillin and other β-lactam antibiotics, which acylate the active site serine. Examples are known from peptidase families S11, S12 and S13. Distinct from EC 3.4.17.14, zinc D-Ala-D-Ala carboxypeptidase
References:
1.  Ghuysen, J.-M., Frère, J.-M., Leyh-Bouille, M., Nguyen-Distèche, M., Coyette, J., Dusart, J., Joris, B., Duez, C., Dideberg, O., Charlier, P., Dive, G. and Lamotte-Brasseur, J. Bacterial wall peptidoglycan, DD-peptidases and β-lactam antibiotics. Scand. J. Infect. Dis. Suppl. 42 (1984) 17–37. [PMID: 6597561]
2.  Frère, J.M. and Joris, B. Penicillin-sensitive enzymes in peptidoglycan biosynthesis. CRC Crit. Rev. Microbiol. 11 (1985) 306–331. [PMID: 3888533]
[EC 3.4.16.4 created 1989]
 
 
EC 3.4.16.5     
Accepted name: carboxypeptidase C
Reaction: Release of a C-terminal amino acid with broad specificity
Other name(s): carboxypeptidase Y; serine carboxypeptidase I; cathepsin A; lysosomal protective protein; deamidase; lysosomal carboxypeptidase A; phaseolin
Comments: A carboxypeptidase with optimum pH 4.5-6.0, inhibited by diisopropyl fluorophosphate, and sensitive to thiol-blocking reagents (reviewed in [1]). Widely distributed in eukaryotes. Type example of peptidase family S10.
References:
1.  Breddam, K. Serine carboxypeptidases. A review. Carlsberg Res. Commun. 51 (1986) 83–128.
2.  Valls, L.A., Hunter, C.P., Rothman, J.H. and Stevens, T.H. Protein sorting in yeast: the localization determinant of yeast vacuolar carboxypeptidase Y resides in the propeptide. Cell 48 (1987) 887–897. [PMID: 3028649]
3.  Jackman, H.L., Morris, P.W., Deddish, P.A., Skidgel, R.A. and Erdös, E.G. Inactivation of endothelin I by deamidase (lysosomal protective protein). J. Biol. Chem. 267 (1992) 2872–2875. [PMID: 1737744]
4.  Miller, J.J., Changaris, D.G. and Levy, R.S. Purification, subunit structure and inhibitor profile of cathepsin-A. J. Chromatogr. 627 (1992) 153–162. [PMID: 1487525]
[EC 3.4.16.5 created 1972 as EC 3.4.12.1, transferred 1978 to EC 3.4.16.1, part transferred 1993 to EC 3.4.16.5 (EC 3.4.16.3 created 1972 as EC 3.4.12.12, transferred 1978 to EC 3.4.16.3, transferred 1992 to EC 3.4.16.1), (EC 3.4.21.13 created 1972, transferred 1978 to EC 3.4.16.1)]
 
 
EC 3.4.16.6     
Accepted name: carboxypeptidase D
Reaction: Preferential release of a C-terminal arginine or lysine residue
Other name(s): cereal serine carboxypeptidase II; Saccharomyces cerevisiae KEX1 gene product; carboxypeptidase Kex1; gene KEX1 serine carboxypeptidase; KEX1 carboxypeptidase; KEX1 proteinase; KEX1DELTAp; CPDW-II; serine carboxypeptidase (misleading); Phaseolus proteinase
Comments: A carboxypeptidase with optimum pH 4.5-6.0, inhibited by diisopropyl fluorophosphate, and sensitive to thiol-blocking reagents (reviewed in [1]). In peptidase family S10 (carboxypeptidase C family).
References:
1.  Breddam, K. Serine carboxypeptidases. A review. Carlsberg Res. Commun. 51 (1986) 83–128.
2.  Breddam, K., Sørensen, S.B. and Svendsen, I. Primary structure and enzymatic properties of carboxypeptidase II from wheat bran. Carlsberg Res. Commun. 52 (1987) 297–311.
3.  Dmochowska, A., Dignard, D., Henning, D., Thomas, D.Y. and Bussey, H. Yeast KEX1 gene encodes a putative protease with a carboxypeptidase B-like function involved in killer toxin and α-factor precursor processing. Cell 50 (1987) 573–584. [PMID: 3301004]
4.  Liao, D.-I., Breddam, K., Sweet, R.M., Bullock, T. and Remington, S.J. Refined atomic model of wheat serine carboxypeptidase II at 2.2-Å resolution. Biochemistry 31 (1992) 9796–9812. [PMID: 1390755]
[EC 3.4.16.6 created 1972 as EC 3.4.12.1, transferred 1978 to EC 3.4.16.1, part transferred 1993 to EC 3.4.16.6 (EC 3.4.16.3 created 1972 as EC 3.4.12.12, transferred 1978 to EC 3.4.16.3, transferred 1992 to EC 3.4.16.1), (EC 3.4.21.13 created 1972, transferred 1978 to EC 3.4.16.1), modified 2011]
 
 
EC 3.4.17.1     
Accepted name: carboxypeptidase A
Reaction: Release of a C-terminal amino acid, but little or no action with -Asp, -Glu, -Arg, -Lys or -Pro
Other name(s): carboxypolypeptidase; pancreatic carboxypeptidase A; tissue carboxypeptidase A
Comments: A zinc enzyme formed from procarboxypeptidase A. Isolated from cattle, pig and dogfish pancreas, and other sources including mast cells [3] and skeletal muscle [4]. Type example of peptidase family M14.
References:
1.  Petra, P.H. Bovine procarboxypeptidase and carboxypeptidase A. Methods Enzymol. 19 (1970) 460–503.
2.  Reeck, G.R., Walsh, K.A. and Neurath, H. Isolation and characterization of carboxypeptidases A and B from activated pancreatic juice. Biochemistry 10 (1971) 4690–4698. [PMID: 5140186]
3.  Everitt, M.T. and Neurath, H. Rat peritoneal mast cell carboxypeptidase: localization, purification and enzymatic properties. FEBS Lett. 110 (1980) 292–296. [PMID: 7371832]
4.  Bodwell, J.E. and Meyer, W.L. Purification and characterization of carboxypeptidase A from rat skeletal muscle. Biochemistry 20 (1981) 2767–2777. [PMID: 7018567]
[EC 3.4.17.1 created 1961 as EC 3.4.2.1, transferred 1972 to EC 3.4.12.2, transferred 1978 to EC 3.4.17.1]
 
 
EC 3.4.17.2     
Accepted name: carboxypeptidase B
Reaction: Preferential release of a C-terminal lysine or arginine amino acid
Other name(s): protaminase; pancreatic carboxypeptidase B; tissue carboxypeptidase B; peptidyl-L-lysine [L-arginine]hydrolase
Comments: A zinc enzyme formed from procarboxypeptidase B. Isolated from cattle, pig and dogfish pancreas and other sources, including skin fibroblasts [3] and adrenal medulla [4]. In peptidase family M14 (carboxypeptidase A family).
References:
1.  Folk, J.E. Carboxypeptidase B (porcine pancreas). Methods Enzymol. 19 (1970) 504–508.
2.  Brodrick, J.W., Geokas, M.C. and Largman, C. Human carboxypeptidase B. II. Purification of the enzyme from pancreatic tissue and comparison with the enzymes present in pancreatic secretion. Biochim. Biophys. Acta 452 (1976) 468–481. [PMID: 1009123]
3.  Butterworth, J. and Duncan, J.J. Carboxypeptidase B activity of cultured skin fibroblasts and relationship to cystic fibrosis. Clin. Chim. Acta 97 (1979) 39–43. [PMID: 40714]
4.  Wallace, E.F., Evans, C.J., Jurik, S.M., Mefford, I.N. and Barchas, J.D. Carboxypeptidase B activity from adrenal medulla. Is it involved in the processing of proenkephalin? Life Sci. 31 (1982) 1793–1796. [PMID: 6130442]
[EC 3.4.17.2 created 1961 as EC 3.4.2.2, transferred 1972 to EC 3.4.12.3, transferred 1978 to EC 3.4.17.2]
 
 
EC 3.4.17.3     
Accepted name: lysine carboxypeptidase
Reaction: Release of a C-terminal basic amino acid, preferentially lysine
Other name(s): carboxypeptidase N; arginine carboxypeptidase; kininase I; anaphylatoxin inactivator; plasma carboxypeptidase B; creatine kinase conversion factor; bradykinase; kininase Ia; hippuryllysine hydrolase; bradykinin-decomposing enzyme; protaminase; CPase N; creatinine kinase convertase; peptidyl-L-lysine(-L-arginine) hydrolase; CPN
Comments: A zinc enzyme found in plasma. Inactivates bradykinin and anaphylatoxins in blood plasma. In peptidase family M14 (carboxypeptidase A family).
References:
1.  Plummer, T.H., Jr. and Erdös, E.G. Human plasma carboxypeptidase N. Methods Enzymol. 80 (1981) 442–449. [PMID: 7341915]
2.  Levin, Y., Skidgel, R.A. and Erdös, E.G. Isolation and characterization of the subunits of human plasma carboxypeptidase N (kininase I). Proc. Natl. Acad. Sci. USA 79 (1982) 4618–4622. [PMID: 6750606]
3.  Skidgel, R.A. Basic carboxypeptidases: regulators of peptide hormone activity. Trends Pharmacol. Sci. 9 (1988) 301–303. [PMID: 3074547]
[EC 3.4.17.3 created 1972 as EC 3.4.12.7, transferred 1978 to EC 3.4.17.3, modified 1989]
 
 
EC 3.4.17.4     
Accepted name: Gly-Xaa carboxypeptidase
Reaction: Release of a C-terminal amino acid from a peptide in which glycine is the penultimate amino acid, e.g. Z-Gly┼Leu
Other name(s): glycine carboxypeptidase; carboxypeptidase a; carboxypeptidase S; peptidase α; yeast carboxypeptidase; Gly-X carboxypeptidase
Comments: From yeast. In peptidase family M20 (glutamate carboxypeptidase family).
References:
1.  Félix, F. and Brouillet, N. Purification et proprietes de deux peptidases de levure de brasserie. Biochim. Biophys. Acta 122 (1966) 127–144. [PMID: 4961236]
2.  Wolf, D.H. and Ehmann, C. Carboxypeptidase S from yeast: regulation of its activity during vegetative growth and differentiation. FEBS Lett. 91 (1978) 59–62. [PMID: 352726]
[EC 3.4.17.4 created 1961 as EC 3.4.2.3, transferred 1972 to EC 3.4.12.8, transferred 1978 to EC 3.4.17.4 (EC 3.4.17.9 created 1981, incorporated 1992)]
 
 
EC 3.4.17.5      
Deleted entry: aspartate carboxypeptidase
[EC 3.4.17.5 created 1972 as EC 3.4.12.9, transferred 1978 to EC 3.4.17.5, deleted 1992]
 
 
EC 3.4.17.6     
Accepted name: alanine carboxypeptidase
Reaction: Release of a C-terminal alanine from a peptide or a variety of pteroyl or acyl groups
Other name(s): N-benzoyl-L-alanine-amidohydrolase
Comments: From soil bacteria. The enzyme from Corynebacterium equi also hydrolyses N-benzoylglycine and N-benzoyl-L-aminobutyric acid.
References:
1.  Levy, C.C. and Goldman, P. Bacterial peptidases. J. Biol. Chem. 244 (1969) 4467–4472. [PMID: 5806587]
2.  Miyagawa, E., Takahiro, H. and Yoshinobu, M. Purification and properties of N-benzoyl-L-alanine amidohydrolase from Corynebacterium equii. Agric. Biol. Chem. 50 (1986) 1527–1531.
[EC 3.4.17.6 created 1972 as EC 3.4.12.11, transferred 1978 to EC 3.4.17.6]
 
 
EC 3.4.17.7      
Transferred entry: acylmuramoyl-alanine carboxypeptidase. Now EC 3.5.1.28, N-acetylmuramoyl-L-alanine amidase
[EC 3.4.17.7 created 1978, deleted 1992]
 
 
EC 3.4.17.8     
Accepted name: muramoylpentapeptide carboxypeptidase
Reaction: Cleavage of the bond UDP-N-acetylmuramoyl-L-alanyl-γ-D-glutamyl-6-carboxy-L-lysyl-D-alanyl┼D-alanine
Other name(s): D-alanine carboxypeptidase I; DD-carboxypeptidase; D-alanine carboxypeptidase; D-alanyl-D-alanine carboxypeptidase; D-alanine-D-alanine-carboxypeptidase; carboxypeptidase D-alanyl-D-alanine; carboxypeptidase I; UDP-N-acetylmuramoyl-tetrapeptidyl-D-alanine alanine-hydrolase; D-alanyl-D-alanine peptidase; DD-peptidase; penicillin binding protein 5; PBP5; PdcA; VanY
Comments: A bacterial enzyme that requires a divalent cation for activity. Does not cleave the C-terminal D-alanine from the product of the above reaction, UDP-N-acetyl-muramoyl-L-alanyl-γ-D-glutamyl-6-carboxy-L-lysyl-D-alanine. Competitively inhibited by penicillins and cephalosporins.
References:
1.  Izaki, K. and Strominger, J.L. Biosynthesis of the peptidoglycan of bacterial cell walls. XIV. Purification and properties of two D-alanine carboxypeptidases from Escherichia coli. J. Biol. Chem. 243 (1968) 3193–3201. [PMID: 4871206]
[EC 3.4.17.8 created 1972 as EC 3.4.12.6, transferred 1978 to EC 3.4.17.8]
 
 
EC 3.4.17.9      
Transferred entry: carboxypeptidase S. Now included with EC 3.4.17.4, Gly-Xaa carboxypeptidase
[EC 3.4.17.9 created 1981, deleted 1992]
 
 
EC 3.4.17.10     
Accepted name: carboxypeptidase E
Reaction: Release of C-terminal arginine or lysine residues from polypeptides
Other name(s): carboxypeptidase H; enkephalin convertase; cobalt-stimulated chromaffin granule carboxypeptidase; insulin granule-associated carboxypeptidase; enkephalin convertase; membrane-bound carboxypeptidase; carboxypeptidase E; enkephalin-precursor endopeptidase; enkephalin precursor carboxypeptidase; peptidyl-L-lysine(-L-arginine) hydrolase
Comments: A zinc enzyme, activated by Co2+. Inhibited by 1,10-phenanthroline and other chelating agents. pH optimum 5.6. Located in storage granules of secretory cells, and active in processing of protein hormones and bioactive peptides. In peptidase family M14 (carboxypeptidase A family).
References:
1.  Qian, Y.M., Varlamov, O. and Fricker, L.D. Glu300 of rat carboxypeptidase E is essential for enzymatic activity but not substrate binding or routing to the regulated secretory pathway. J. Biol. Chem. 274 (1999) 11582–11586. [PMID: 10206965]
2.  Fricker, L.D. Carboxypeptidase E/H. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 1341–1344.
3.  Fricker, L.D. Methods for studying carboxypeptidase E. Methods Neurosci. 23 (1995) 237–250.
4.  Manser, E., Fernandez, D. , Loo,L., Goh, P.Y., Monfries, C., Hall, C. and Lim, L. Human carboxypeptidase E: isolation and characterisaton of the cDNA, sequence conservation, expression and processing in vitro. Biochem. J. 267 (1990) 517–525. [PMID: 2334405]
5.  Fricker, L.D. Carboxypeptidase E. Annu. Rev. Physiol. 50 (1988) 309–321. [PMID: 2897826]
[EC 3.4.17.10 created 1986, modified 2000]
 
 
EC 3.4.17.11     
Accepted name: glutamate carboxypeptidase
Reaction: Release of C-terminal glutamate residues from a wide range of N-acylating moieties, including peptidyl, aminoacyl, benzoyl, benzyloxycarbonyl, folyl and pteroyl groups
Other name(s): carboxypeptidase G; carboxypeptidase G1; carboxypeptidase G2; glutamyl carboxypeptidase; N-pteroyl-L-glutamate hydrolase
Comments: A zinc enzyme produced by pseudomonads, Flavobacterium sp. and Acinetobacter sp. Its ability to hydrolyse pteroyl-L-glutamate (folic acid) has led to its use as a folate-depleting, antitumour agent. Type example of peptidase family M20
References:
1.  Goldman, P. and Levy, C.C. Carboxypeptidase G: purification and properties. Proc. Natl Acad. Sci. USA 58 (1967) 1299–1306. [PMID: 5237864]
2.  McCullogh, J.L., Chabner, B.A. and Bertino, J.R. Purification and properties of carboxypeptidase G1. J. Biol. Chem. 246 (1971) 7207–7213. [PMID: 5129727]
3.  Albrecht, A.M., Boldizar, E. and Hutchinson, D.J. Carboxypeptidase displaying differential velocity in hydrolysis of methotrexate, 5-methyltetrahydrofolic acid, and leucovorin. J. Bacteriol. 134 (1978) 506–513. [PMID: 26657]
4.  Sherwood, R.F., Melton, R.G. and Alwan, S.A. Purification and properties of carboxypeptidase G2 from Pseudomonas sp. strain RS-16. Eur. J. Biochem. 148 (1985) 447–453. [PMID: 3838935]
[EC 3.4.17.11 created 1992]
 
 
EC 3.4.17.12     
Accepted name: carboxypeptidase M
Reaction: Cleavage of C-terminal arginine or lysine residues from polypeptides
Other name(s): CPM
Comments: A membrane-bound enzyme optimally active at neutral pH. In peptidase family M14 (carboxypeptidase A family)
References:
1.  Skidgel, R.A. Basic carboxypeptidases: Regulators of peptide hormone activity. Trends Pharmacol. Sci. 9 (1988) 303–304. [PMID: 3074547]
2.  Deddish, P.A., Skidgel, R.A. and Erdös, E.G. Enhanced Co2+ activation and inhibitor binding of carboxypeptidase M at low pH. Biochem. J. 261 (1989) 289–291. [PMID: 2775217]
3.  Skidgel, R.A., Davis, R.M. and Tan, F. Human carboxypeptidase M. Purification and characterization of membrane-bound carboxypeptidase that cleaves peptide hormones. J. Biol. Chem. 264 (1989) 2236–2241. [PMID: 2914904]
[EC 3.4.17.12 created 1992]
 
 
EC 3.4.17.13     
Accepted name: muramoyltetrapeptide carboxypeptidase
Reaction: Hydrolysis of the bond: N-acetyl-D-glucosaminyl-N-acetylmuramoyl-L-Ala-D-glutamyl-6-carboxy-L-lysyl┼D-alanine
Other name(s): carboxypeptidase IIW; carboxypeptidase II; lysyl-D-alanine carboxypeptidase; L-lysyl-D-alanine carboxypeptidase; LD-carboxypeptidase
Comments: Variants are known from various microorganisms. Involved in peptidoglycan synthesis, catalysing both decarboxylation and transpeptidation. Stimulated by divalent cations such as Mg2+ and Ca2+, but not by Zn2+. Inhibited by thiol-blocking reagents, but unaffected by penicillin
References:
1.  DasGupta, H. and Fan, D.P. Purification and characterization of a carboxypeptidase-transpeptidase of Bacillus megaterium acting on the tetrapeptide moiety of the peptidoglycan. J. Biol. Chem. 254 (1979) 5672–5683. [PMID: 109439]
2.  Rousset, A., Nguyen-Disteche, M., Minck, R. and Ghuysen, J.-M. Penicillin-binding proteins and carboxypeptidase/transpeptidase activities in Proteus vulgaris P18 and its penicillin-induced stable L-forms. J. Bacteriol. 152 (1982) 1042–1048. [PMID: 6754695]
3.  Metz, R., Henning, S. and Hammes, W.P. LD-Carboxypeptidase activity in Escherichia coli. II. Isolation, purification and characterization of the enzyme from E. coli K 12. Arch. Microbiol. 144 (1986) 181–186. [PMID: 3521530]
[EC 3.4.17.13 created 1992]
 
 
EC 3.4.17.14     
Accepted name: zinc D-Ala-D-Ala carboxypeptidase
Reaction: Cleavage of the bond: (Ac)2-L-lysyl-D-alanyl┼D-alanine
Other name(s): Zn2+ G peptidase, D-alanyl-D-alanine hydrolase; D-alanyl-D-alanine-cleaving carboxypeptidase; DD-carboxypeptidase; G enzyme; DD-carboxypeptidase-transpeptidase
Comments: A zinc enzyme. Catalyses carboxypeptidation but not transpeptidation reactions involved in bacterial cell wall metabolism. Weakly inhibited by β-lactams. In peptidase family M15. Distinct from EC 3.4.16.4, serine-type D-Ala-D-Ala carboxypeptidase.
References:
1.  Dideberg, O., Charlier, P., Dive, G., Joris, B., Frère, J.M. and Ghuysen, J.M. Structure of a Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase at 2.5 Å resolution. Nature 299 (1982) 469–470. [PMID: 7121588]
2.  Joris, B., Van Beeumen, J., Casagrande, F., Gerday, C., Frère, J.-M. and Ghuysen, J.-M. The complete amino acid sequence of the Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase of Streptomyces albus G. Eur. J. Biochem. 130 (1983) 53–69. [PMID: 6825689]
3.  Ghuysen, J.-M., Frère, J.-M., Leyh-Bouille, M., Nguyen-Distèche, M., Coyette, J., Dusart, J., Joris, B., Duez, C., Dideberg, O., Charlier, P., Dive, G. and Lamotte-Brasseur, J. Bacterial wall peptidoglycan, DD-peptidases and β-lactam antibiotics. Scand. J. Infect. Dis. Suppl. 42 (1984) 17–37. [PMID: 6597561]
[EC 3.4.17.14 created 1992]
 
 
EC 3.4.17.15     
Accepted name: carboxypeptidase A2
Reaction: Similar to that of carboxypeptidase A (EC 3.4.17.1), but with a preference for bulkier C-terminal residues
Other name(s): CPA2
Comments: Isolated from rat pancreas but not present in cattle pancreas. In peptidase family M14 (carboxypeptidase A family).
References:
1.  Gardell, S.J., Craik, C.S., Clauser, E., Goldsmith, E.J., Stewart, C.B., Graf, M. and Rutter, W.J. A novel rat carboxypeptidase, CPA2: characterization, molecular cloning, and evolutionary implications on substrate specificity in the carboxypeptidase gene family. J. Biol. Chem. 263 (1988) 17828–17836. [PMID: 3182871]
[EC 3.4.17.15 created 1992]
 
 
EC 3.4.17.16     
Accepted name: membrane Pro-Xaa carboxypeptidase
Reaction: Release of a C-terminal residue other than proline, by preferential cleavage of a prolyl bond
Other name(s): carboxypeptidase P; microsomal carboxypeptidase; membrane Pro-X carboxypeptidase
Comments: One of the renal brush border exopeptidases
References:
1.  Dehm, P. and Nordwig, A. The cleavage of prolyl peptides by kidney peptidases. Isolation of a microsomal carboxypeptidase from swine kidney. Eur. J. Biochem. 17 (1970) 372–377. [PMID: 5500406]
2.  Booth, A.G., Hubbard, L.M.L. and Kenny, A.J. Proteins of the kidney microvillar membrane. Immunoelectrophoretic analysis of the membrane hydrolase: identification and resolution of the detergent- and proteinase-solubilized forms. Biochem. J. 179 (1979) 397–405. [PMID: 486090]
3.  Hedeager-Sorensen, S. and Kenny, A.J. Proteins of the kidney microvillar membrane. Purification and properties of carboxypeptidase P from pig kidneys. Biochem. J. 229 (1985) 251–257. [PMID: 4038259]
[EC 3.4.17.16 created 1992]
 
 
EC 3.4.17.17     
Accepted name: tubulinyl-Tyr carboxypeptidase
Reaction: Cleavage of the -Glu┼Tyr bond to release the C-terminal tyrosine residue from the native tyrosinated tubulin. Inactive on Z-Glu-Tyr
Other name(s): carboxypeptidase-tubulin; soluble carboxypeptidase; tubulin-tyrosine carboxypeptidase; tubulin carboxypeptidase; tubulinyltyrosine carboxypeptidase; tyrosinotubulin carboxypeptidase; tyrosyltubulin carboxypeptidase; TTCPase; brain I carboxypeptidase
Comments: Active at neutral pH, from brain
References:
1.  Argaraña, C.E., Barra, H.S. and Caputto, R. Tubulinyl-tyrosine carboxypeptidase from chicken brain: properties and partial purification. J. Neurochem. 34 (1980) 114–118. [PMID: 7452228]
2.  Kumar, N. and Flavin, M. Preferential action of a brain detyrosinolating carboxypeptidase on polymerized tubulin. J. Biol. Chem. 256 (1981) 7678–7686. [PMID: 6114100]
3.  Arce, C.A. and Barra, H.S. Association of tubulinyl-tyrosine carboxypeptidase with microtubules. FEBS Lett. 157 (1983) 75–78. [PMID: 6862022]
[EC 3.4.17.17 created 1992]
 
 
EC 3.4.17.18     
Accepted name: carboxypeptidase T
Reaction: Releases a C-terminal residue, which may be hydrophobic or positively charged
Other name(s): CPT
Comments: Known from Thermoactinomyces vulgaris. In peptidase family M14 (carboxypeptidase A family)
References:
1.  Osterman, A.L., Stepanov, V.M., Rudenskaya, G.N., Khodova, O.M., Tsaplina, I.A., Yakovleva, M.B. and Loginova, L.G. Carboxypeptidase T - an extracellular carboxypeptidase of thermophilic actinomycetes - a remote analog of animal carboxypeptidases. Biochemistry (USSR) 49 (1984) 292–301. [PMID: 6424730]
2.  Smulevitch, S.V., Osterman, A.L., Galperina, O.V., Matz, M.V., Zagnitko, O.P., Kadyrov, R.M., Tsaplina, I.A., Grishin, N.V., Chestukhina, G.G. and Stepanov, V.M. Molecular cloning and primary structure of Thermoactinomyces vulgaris carboxypeptidase T: a metalloenzyme endowed with dual substrate specificity. FEBS Lett. 291 (1991) 75–78. [PMID: 1936254]
3.  Teplyakov, A., Polyakov, K., Obmolova, G., Strokopytov, B., Kuranova, I., Osterman, A., Grishin, N., Smulevitch, S., Zagnitko, O., Galperina, O., Matz, M. and Stepanov, V. Crystal structure of carboxypeptidase T from Thermoactinomyces vulgaris. Eur. J. Biochem. 208 (1992) 281–288. [PMID: 1521526]
[EC 3.4.17.18 created 1993]
 
 
EC 3.4.17.19     
Accepted name: carboxypeptidase Taq
Reaction: Release of a C-terminal amino acid with broad specificity, except for -Pro
Comments: A 56-kDa enzyme from Thermus aquaticus. Most active at 80° C. Type example of peptidase family M32
References:
1.  Lee, S.-H., Minagawa, E., Taguchi, H., Matsuzawa, H., Ohta, T., Kaminogawa, S. and Yamauchi, K. Purification and characterization of a thermostable carboxypeptidase (carboxypeptidase Taq) from Thermus aquaticus YT-1. Biosci. Biotechnol. Biochem. 56 (1992) 1839–1844. [PMID: 1369078]
2.  Lee, S.-H., Taguchi, H., Yoshimura, E., Minagawa, E., Kaminogawa, S., Ohta, T. and Matsuzawa, H. Carboxypeptidase Taq, a thermostable zinc enzyme, from Thermus aquaticus YT-1: molecular cloning, sequencing, and expression of the encoding gene in Escherichia coli. Biosci. Biotechnol. Biochem. 58 (1994) 1490–1495. [PMID: 7765282]
[EC 3.4.17.19 created 1996]
 
 
EC 3.4.17.20     
Accepted name: carboxypeptidase U
Reaction: Release of C-terminal Arg and Lys from a polypeptide
Other name(s): arginine carboxypeptidase; carboxypeptidase R; plasma carboxypeptidase B (misleading, since the term carboxypeptidase B is used for other enzymes); thrombin-activatable fibrinolysis inhibitor
Comments: Pro-carboxypeptidase U in (human) plasma is activated by thrombin or plasmin during clotting to form the unstable carboxypeptidase U, with activity similar to that of the more stable lysine carboxypeptidase, except that no preference is shown for Lys over Arg. A zinc enzyme, in peptidase family M14 (carboxypeptidase A family)
References:
1.  Eaton, D.L., Malloy, B.E., Tsai, S.P., Henzel, W. and Drayna, D. Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. J. Biol. Chem. 266 (1991) 21833–21838. [PMID: 1939207]
2.  Shinohara, T., Sakurada, C., Suzuki, T., Takeuchi, O., Campbell, W., Ikeda, S., Okada, N. and Okada, H. Pro-carboxypeptidase R cleaves bradykinin following activation. Int. Arch. Allergy Immunol. 103 (1994) 400–404. [PMID: 8130654]
3.  Wang, W., Hendriks, D.F. and Scharpé, S. Carboxypeptidase U, a plasma carboxypeptidase with high affinity for plasminogen. J. Biol. Chem. 269 (1994) 15937–15944. [PMID: 8195249]
4.  Tan, A.K. and Eaton, D.L. Activation and characterization of procarboxypeptidase B from human plasma. Biochemistry 34 (1995) 5811–5816. [PMID: 7727441]
5.  Broze, G.J., Jr. and Higuchi, D.A. Coagulation-dependent inhibition of fibrinolysis: Role of carboxypeptidase U and the premature lysis of clots from hemophilic plasma. Blood 88 (1996) 3815–3823. [PMID: 8916945]
[EC 3.4.17.20 created 1997]
 
 
EC 3.4.17.21     
Accepted name: glutamate carboxypeptidase II
Reaction: Release of an unsubstituted, C-terminal glutamyl residue, typically from Ac-Asp-Glu or folylpoly-γ-glutamates
Glossary: quisqualic acid = 3-(3,5-dioxo-1,2,4-oxazadiazolidin-2-yl)Ala
Other name(s): N-acetylated-γ-linked-acidic dipeptidase (NAALADase); folate hydrolase; prostate-specific membrane antigen; pteroylpoly-γ-glutamate carboxypeptidase; microsomal γ-glutamyl carboxypeptidase; pteroylpolyglutamate hydrolase; folylpolyglutamate hydrolase; pteroylpoly-γ-glutamate hydrolase; pteroylpolyγglutamyl hydrolase; pteroylpolyglutamate hydrolase; pteroylpolyglutamic acid hydrolase; PSM antigen; acetylaspartylglutamate dipeptidase; NAALA dipeptidase; rat NAAG peptidase; mGCP; membrane glutamate carboxypeptidase; N-acetylated-α-linked-amino dipeptidase; prostrate-specific membrane antigen; N-Acetylated α-linked acidic dipeptidase; PSMA
Comments: A metallo-carboxypeptidase that is predominantly expressed as a membrane-bound enzyme of 94-100 kDa , but also exists in a soluble form. Hydrolyses α-peptide bonds in Ac-Asp-Glu, Asp-Glu, and Glu-Glu, but also γ-glutamyl bonds in γ-Glu-Glu, and folylpoly-γ-glutamates. With folylpoly-γ-glutamates, shows processive carboxypeptidase activity to produce pteroylmonoglutamate [4]. Does not hydrolyse Ac-β-Asp-Glu. Known inhibitors: quisqualic acid, Ac-β-Asp-Glu, and 2-phosphonomethyl-pentanedioate. In peptidase family M28 of Vibrio leucyl aminopeptidase. The release of C-terminal glutamate from folylpoly-γ-glutamates is also catalysed by EC 3.4.17.11 (glutamate carboxypeptidase) and EC 3.4.19.9 (γ-Glu-X carboxypeptidase).
References:
1.  Heston, W.D.W. Characterization and glutamyl preferring carboxypeptidase function of prostate specific membrane antigen: a novel folate hydrolase. Urology 49 (1997) 104–112. [PMID: 9123729]
2.  Rawlings, N.D. and Barrett, A.J. Structure of membrane glutamate carboxypeptidase. Biochim. Biophys. Acta 1339 (1997) 247–252. [PMID: 9187245]
3.  Halsted, C.H., Ling, E.-H., Luthi-Carter, R., Villanueva, J.A., Gardner, J.M., Coyle, J.T. Folylpoly-γ-glutamate carboxypeptidase from pig jejunum: molecular characterization and relation to glutamate carboxypeptidase II. J. Biol. Chem. 273 (1998) 20417–20424. [PMID: 9685395]
4.  Luthi-Carter, R., Berger, U.V., Barczak, A.K., Enna, M. and Coyle, J.T. Isolation and expression of a rat brain cDNA encoding glutamate carboxypeptidase II. Proc. Natl. Acad. Sci. USA 95 (1998) 3215–3220. [PMID: 9501243]
[EC 3.4.17.21 created 1997, modified 2000 (EC 3.4.13.8 created 1972 and EC 3.4.19.8 created 1992, incorporated 2000)]
 
 
EC 3.4.17.22     
Accepted name: metallocarboxypeptidase D
Reaction: Releases C-terminal Arg and Lys from polypeptides
Other name(s): carboxypeptidase D (cattle, human, mouse, rat); gp180 (duck)
Comments: Activated by Co2+; inhibited by guanidinoethylmercaptosuccinic acid. Large molecule (180 kDa) because of presence of three copies of metallopeptidase domain. The product of the silver gene (Drosophila) is similar. A zinc metallopeptidase in peptidase family M14 (carboxypeptidase A family)
References:
1.  Kuroki, K., Eng, F., Ishikawa, T., Turck, C., Harada, F. and Ganem, D. gp180, a host cell glycoprotein that binds duck hepatitis B virus particles, is encoded by a member of the carboxypeptidase gene family. J. Biol. Chem. 270 (1995) 15022–15028. [PMID: 9525948]
2.  Song, L.X. and Fricker, L.D. Purification and characterization of carboxypeptidase D, a novel carboxypeptidase E-like enzyme, from bovine pituitary. J. Biol. Chem. 270 (1995) 25007–25013. [PMID: 7559630]
3.  Song, L.X. and Fricker, L.D. Tissue distribution and characterization of soluble and membrane-bound forms of metallocarboxypeptidase D. J. Biol. Chem. 271 (1996) 28884–28889. [PMID: 8910535]
[EC 3.4.17.22 created 1997]
 
 
EC 3.4.17.23     
Accepted name: angiotensin-converting enzyme 2
Reaction: angiotensin II + H2O = angiotensin-(1–7) + L-phenylalanine
Other name(s): ACE-2; ACE2; hACE2; angiotensin converting enzyme 2; angiotensin converting enzyme-2; Tmem27
Comments: A transmembrane glycoprotein with an extracellular catalytic domain. Angiotensin-converting enzyme 2 functions as a carboxypeptidase, cleaving a single C-terminal residue from a distinct range of substrates [2]. Catalytic efficiency is 400-fold higher with angiotensin II (1–8) as a substrate than with angiotensin I (1–10). Angiotensin-converting enzyme 2 also efficiently hydrolyses des-Arg9-bradykinin, but it does not hydrolyse bradykinin [1]. In peptidase family M2.
References:
1.  Vickers, C., Hales, P., Kaushik, V., Dick, L., Gavin, J., Tang, J., Godbout, K., Parsons, T., Baronas, E., Hsieh, F., Acton, S., Patane, M., Nichols, A. and Tummino, P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J. Biol. Chem. 277 (2002) 14838–14843. [PMID: 11815627]
2.  Lambert, D.W., Hooper, N.M. and Turner, A.J. Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. Biochem. Pharmacol. 75 (2008) 781–786. [PMID: 17897633]
3.  Towler, P., Staker, B., Prasad, S.G., Menon, S., Tang, J., Parsons, T., Ryan, D., Fisher, M., Williams, D., Dales, N.A., Patane, M.A. and Pantoliano, M.W. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J. Biol. Chem. 279 (2004) 17996–18007. [PMID: 14754895]
[EC 3.4.17.23 created 2009]
 
 
EC 3.4.18.1     
Accepted name: cathepsin X
Reaction: Release of C-terminal amino acid residues with broad specificity, but lacks action on C-terminal proline. Shows weak endopeptidase activity
Other name(s): cathepsin B2; cysteine-type carboxypeptidase; cathepsin IV; cathepsin Z; acid carboxypeptidase; lysosomal carboxypeptidase B
Comments: Cathepsin X is a lysosomal cysteine peptidase of family C1 (papain family). The pH optimum is dependent on the substrate and is 5.0 for the carboxypeptidase activity. Unstable above pH 7.0. Compound E-64, leupeptin and antipain are inhibitors, but not cystatin C. Cathepsin X is ubiquitously distributed in mammalian tissues. The propeptide is extremely short (38 amino acid residues) and the proenzyme is catalytically active. Human gene locus: 20q13.
References:
1.  Nägler, D.K., Zhang, R., Tam, W., Sulea, T., Purisima, E.O. and Ménard, R. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. Biochemistry 38 (1999) 12648–12654. [PMID: 10504234]
2.  Nägler, D.K. and Ménard, R. Human cathepsin X: A novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Lett. 434 (1998) 135–139. [PMID: 9738465]
3.  Santamaría, I. Velasco, G., Pendás, A.M., Fueyo, A. and López-Otín, C. Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location. J. Biol. Chem. 273 (1998) 16816–16823. [PMID: 9642240]
4.  McDonald, J.K. and Ellis, S. On the substrate specificity of cathepsins B1 and B2 including a new fluorogenic substrate for cathepsin B1. Life Sci. 17 (1975) 1269–1276. [PMID: 577]
5.  Otto, K. and Riesenkönig, H. Improved purification of cathepsin B1 and cathepsin B2. Biochim. Biophys. Acta 379 (1975) 462–475. [PMID: 1122298]
6.  Ninjoor, V., Taylor, S.L. and Tappel, A.L. Purification and characterization of rat liver lysosomal cathepsin B2. Biochim. Biophys. Acta 370 (1974) 308–321. [PMID: 4429705]
[EC 3.4.18.1 created 1981, modified 2000]
 
 
EC 3.4.19.1     
Accepted name: acylaminoacyl-peptidase
Reaction: Cleavage of an N-acetyl or N-formyl amino acid from the N-terminus of a polypeptide
Other name(s): acylamino-acid-releasing enzyme; N-acylpeptide hydrolase; N-formylmethionine (fMet) aminopeptidase; α-N-acylpeptide hydrolase
Comments: Active at neutral pH. Several variants of this enzyme exist; the human erythrocyte enzyme is relatively specific for removal of N-acetylalanine from peptides. Displays dipeptidyl-peptidase activity on glycyl-peptides, perhaps as a result of mis-recognition of the glycyl residue as an uncharged N-acyl group. Inhibited by diisopropyl fluorophosphate. In peptidase family S9 (prolyl oligopeptidase family).
References:
1.  Tsunazawa, S., Narita, K. and Ogata, K. Acylamino acid-releasing enzyme from rat liver. J. Biochem. (Tokyo) 77 (1975) 89–102. [PMID: 1137989]
2.  Ungar, T., Nagelschmidt, M. and Struck, H. N-Acetylaminoacyl-p-nitranilidase from human placenta. Purification and some properties. Eur. J. Biochem. 97 (1979) 205–211. [PMID: 477668]
3.  Kobayashi, K. and Smith, J.A. Acyl-peptide hydrolase from rat liver. Characterization of enzyme reaction. J. Biol. Chem. 262 (1987) 11435–11437. [PMID: 3305492]
[EC 3.4.19.1 created 1978 as EC 3.4.14.3, transferred 1981 to EC 3.4.19.1]
 
 
EC 3.4.19.2     
Accepted name: peptidyl-glycinamidase
Reaction: Cleavage of C-terminal glycinamide from polypeptides
Other name(s): carboxyamidase; peptidyl carboxy-amidase; peptidyl-aminoacylamidase; carboxamidopeptidase; peptidyl amino acid amide hydrolase
Comments: Inactivates vasopressin and oxytocin by splitting off glycinamide. Also cleaves ester substrates of trypsin and chymotrypsin. Although glycinamide is by far the preferred leaving group, other aminoacylamides may also be released, e.g. phenylalaninamide. The toad skin enzyme is inhibited by diisopropyl fluorophosphate.
References:
1.  Fruhaufová, L., Suska-Brezezinska, E., Barth, T. and Rychlik, I. Rat liver enzyme inactivating oxytocin and its deamino-carba analogues. Coll. Czech. Chem. Commun. 38 (1973) 2793–2798.
2.  Nardacci, N.J., Mukhopadhyay, S. and Campbell, B.J. Partial purification and characterization of the antidiuretic hormone in toad bladder. Biochim. Biophys. Acta 377 (1975) 146–157. [PMID: 1122284]
3.  Simmons, W.H. and Walter, R. Carboxamidopeptidase: purificaction and characterization of a neurohypophyseal hormone inactivating peptidase from toad skin. Biochemistry 19 (1980) 39–48. [PMID: 6766314]
[EC 3.4.19.2 created 1978 as EC 3.4.15.2, transferred 1981 to EC 3.4.19.2]
 
 
EC 3.4.19.3     
Accepted name: pyroglutamyl-peptidase I
Reaction: Release of an N-terminal pyroglutamyl group from a polypeptide, the second amino acid generally not being Pro
Other name(s): 5-oxoprolyl-peptidase; pyrase; pyroglutamate aminopeptidase; pyroglutamyl aminopeptidase; L-pyroglutamyl peptide hydrolase; pyrrolidone-carboxyl peptidase; pyrrolidone-carboxylate peptidase; pyrrolidonyl peptidase; L-pyrrolidonecarboxylate peptidase; pyroglutamidase; pyrrolidonecarboxylyl peptidase
Comments: A cysteine peptidase, known from bacteria, plants and animals. The enzyme from bacterial sources is used in protein sequencing, and is the type example of peptidase family C15.
References:
1.  Tsuru, D., Nakamura, K., Yoshimoto, T. and Fujiwara, K. Pyroglutamyl-peptidase from Bacillus amyloliquefaciens. An improved purification method and some properties of the enzyme. Biochim. Biophys. Acta 791 (1984) 117–122.
2.  Awadé, A.C., Cleuziat, P., Gonzalès, T. and Robert-Baudouy, J. Pyrrolidone carboxyl peptidase (Pcp): an enzyme that removes pyroglutamic acid (pGlu) from pGlu-peptides and pGlu-proteins. Proteins: Struct. Funct. Genet. 20 (1994) 34–51. [PMID: 7824521]
3.  Patti, J.M., Schneider, A., Garza, N. and Boles, J.O. Isolation and characterization of pcp, a gene encoding a pyrrolidone carboxyl peptidase in Staphylococcus aureus. Gene 166 (1995) 95–99. [PMID: 8529900]
4.  Le Saux, O., Gonzalès, T. and Robert-Baudouy, J. Mutational analysis of the active site of Pseudomonas fluorescens pyrrolidone carboxyl peptidase. J. Bacteriol. 178 (1996) 3308–3313. [PMID: 8655512]
[EC 3.4.19.3 created 1972 as EC 3.4.11.8, transferred 1981 to EC 3.4.19.3, modified 1997]
 
 
EC 3.4.19.4      
Deleted entry:  N-acetylmethionylpeptide peptidase
[EC 3.4.19.4 created 1989, deleted 1992]
 
 
EC 3.4.19.5     
Accepted name: β-aspartyl-peptidase
Reaction: Cleavage of a β-linked Asp residue from the N-terminus of a polypeptide
Other name(s): β-aspartyl dipeptidase; β-aspartyl peptidase; β-aspartyldipeptidase
Comments: Other isopeptide bonds, e.g. γ-glutamyl and β-alanyl, are not hydrolysed. A mammalian, cytosolic enzyme.
References:
1.  Haley, E.E. β-Aspartyl peptidase from rat liver. Methods Enzymol. 19 (1970) 737–741.
[EC 3.4.19.5 created 1972 as EC 3.4.13.10, transferred 1992 to EC 3.4.19.5, modified 1997]
 
 
EC 3.4.19.6     
Accepted name: pyroglutamyl-peptidase II
Reaction: Release of the N-terminal pyroglutamyl group from pGlu┼His-Xaa tripeptides and pGlu┼His-Xaa-Gly tetrapeptides
Other name(s): thyroliberinase; pyroglutamyl aminopeptidase II; , thyrotropin-releasing factor pyroglutamate aminopeptidase; pyroglutamate aminopeptidase II; pyroglutamyl peptidase II; thyroliberin-hydrolyzing pyroglutamate aminopeptidase; thyrotropin-releasing hormone-degrading pyroglutamate aminopeptidase; thyrotropin-releasing hormone-degrading peptidase; TRH aminopeptidase
Comments: Highly specific for thyrotropin releasing hormone (pyroglutamyl-histidyl-prolylamide). Will not cleave the pyroglutamyl-histidyl bond of luteinizing hormone releasing hormone. Found in serum and brain. Inhibited by metal chelators. In peptidase family M1 (membrane alanyl aminopeptidase family)
References:
1.  Bauer, K. and Nowak, P. Characterization of a thyroliberin-degrading serum enzyme catalyzing the hydrolysis of thyroliberin at the pyroglutamyl-histidine bond. Eur. J. Biochem. 99 (1979) 239–246. [PMID: 115687]
2.  O'Connor, B. and O'Cuinn, G. Purification of and kinetic studies on a narrow specifity synaptosomal membrane pyroglutamate aminopeptidase from guinea-pig brain. Eur. J. Biochem. 150 (1985) 47–52. [PMID: 2862039]
3.  Wilk, S. and Wilk, E.K. Pyroglutamyl peptidase II, a thyrotropin releasing hormone degrading enzyme: purification and specificity studies of the rabbit brain enzyme. Neurochem. Int. 15 (1989) 81–89. [PMID: 20504468]
[EC 3.4.19.6 created 1992]
 
 
EC 3.4.19.7     
Accepted name: N-formylmethionyl-peptidase
Reaction: Release of an N-terminal, formyl-methionyl residue from a polypeptide
Other name(s): (fMet)-releasing enzyme; formylmethionine aminopeptidase
Comments: Highly specific for N-formylmethionyl peptides. Will not cleave methionyl peptides or N-formyl derivatives of amino acids other than methionine. Isolated from rat liver. Inhibited by heavy metals and activated by Cl-
References:
1.  Suda, H., Yamamoto, K., Aoyagi, T. and Umezawa, H. Purification and properties of N-formylmethionine aminopeptidase from rat liver. Biochim. Biophys. Acta 616 (1980) 60–67. [PMID: 7437450]
[EC 3.4.19.7 created 1992]
 
 
EC 3.4.19.8      
Transferred entry: now EC 3.4.17.21, glutamate carboxypeptidase II
[EC 3.4.19.8 created 1992, deleted 2000]
 
 
EC 3.4.19.9     
Accepted name: γ-glutamyl hydrolase
Reaction: Hydrolysis of a γ-glutamyl bond
Other name(s): conjugase; folate conjugase; lysosomal γ-glutamyl carboxypeptidase; γ-Glu-X carboxypeptidase; pteroyl-poly-γ-glutamate hydrolase; carboxypeptidase G; folic acid conjugase; poly(γ-glutamic acid) endohydrolase; polyglutamate hydrolase; poly(glutamic acid) hydrolase II; pteroylpoly-γ-glutamyl hydrolase
Comments: A lysosomal or secreted, thiol-dependent peptidase, most active at acidic pH. Commonly studied with folylpoly-γ-glutamate as substrate, with which the initial cleavage may release glutamate or poly-γ-glutamate of two or more residues, according to the species of origin of the enzyme. Final products are pteroyl-α-glutamate (folic acid) and free glutamate. Highly specific for the γ-glutamyl bond, but not for the C-terminal amino acid (leaving group). Action on γ-glutamyl bonds is independent of an N-terminal pteroyl moiety, but it is not known whether an N-terminal γ-Glu residue can be hydrolysed. Type example of peptidase family C26.
References:
1.  McGuire, J.J. and Coward, J.K. Pteroylpolyglutamates: biosynthesis, degradation and function.. In: Blakley, R.L. and Benkovic, S.J. (Eds), Folates and Pterins, John Wiley and Sons, New York, 1984, pp. 135–191.
2.  Wang, Y., Nimec, Z., Ryan, T.J., Dias, J.A. and Galivan, J. The properties of the secreted γ-glutamyl hydrolases from H35 hepatoma cells. Biochim. Biophys. Acta 1164 (1993) 227–235. [PMID: 8343522]
3.  Yao, R., Rhee, M.S. and Galivan, J. Effects of γ-glutamyl hydrolase on folyl and antifolylpolyglutamates in cultured H35 hepatoma cells. Mol. Pharmacol. 48 (1995) 505–511. [PMID: 7565632]
4.  Yao, R., Schneider, E., Ryan, T.J. and Galivan, J. Human γ-glutamyl hydrolase: cloning and characterization of the enzyme expressed in vitro. Proc. Natl. Acad. Sci. USA 93 (1996) 10134–10138. [PMID: 8816764]
5.  Yao, R., Nimec, Z., Ryan, T.J. and Galivan, J. Identification, cloning, and sequencing of a cDNA coding for rat γ-glutamyl hydrolase. J. Biol. Chem. 271 (1996) 8525–8528. [PMID: 8621474]
[EC 3.4.19.9 created 1972 as EC 3.4.12.10, transferred 1978 to EC 3.4.22.12, transferred 1992 to EC 3.4.19.9, modified 1997]
 
 
EC 3.4.19.10      
Transferred entry: acylmuramoyl-Ala peptidase. Now EC 3.5.1.28, N-acetylmuramoyl-L-alanine amidase
[EC 3.4.19.10 created 1972 as EC 3.4.12.5, transferred 1978 to EC 3.4.17.7, transferred 1992 to EC 3.4.19.10, deleted 1997]
 
 
EC 3.4.19.11     
Accepted name: γ-D-glutamyl-meso-diaminopimelate peptidase
Reaction: Hydrolysis of γ-D-glutamyl bonds to the L-terminus (position 7) of meso-diaminopimelic acid (meso-A2pm) in 7-(L-Ala-γ-D-Glu)-meso-A2pm and 7-(L-Ala-γ-D-Glu)-7-(D-Ala)-meso-A2pm. It is required that the D-terminal amino and carboxy groups of meso-A2pm are unsubstituted
Other name(s): endopeptidase I; γ-D-glutamyldiaminopimelate endopeptidase; γ-D-glutamyl-L-meso-diaminopimelate peptidoglycan hydrolase; γ-glutamyl-L-meso-diaminopimelyl endopeptidase; γ-D-glutamyl-meso-diaminopimelate endopeptidase; γ-D-glutamyl-meso-diaminopimelic peptidoglycan hydrolase; γ-D-glutamyl-meso-diaminopimelic endopeptidase; γ-D-glutamyl-meso-D-aminopimelic endopeptidase
Comments: A 45-kDa metallopeptidase from Bacillus sphaericus, the substrates being components of the bacterial spore wall. A member of peptidase family M14 (carboxypeptidase A family). Endopeptidase II has similar activity, but differs in cellular location, molecular mass and catalytic mechanism [3]
References:
1.  Arminjon, F., Guinand, M., Vacheron, M.-J. and Michel, G. Specificity profiles of the membrane-bound γ-D-glutamyl-(L)meso-diaminopimelate endopeptidase and LD-carboxypeptidase from Bacillus sphaericus 9602. Eur. J. Biochem. 73 (1977) 557–565. [PMID: 849747]
2.  Garnier, M., Vacheron, M.-J., Guinard, M. and Michel, G. Purification and partial characterization of the extracellular γ-D-glutamyl-(L)meso-diaminopimelate endopeptidase I, from Bacillus sphaericus NCTC 9602. Eur. J. Biochem. 148 (1985) 539–543. [PMID: 3922755]
3.  Hourdou, M.-L., Guinand, M., Vacheron, M.-J., Michel, G., Denoroy, L., Duez, C., Englebert, S., Joris, B., Weber, G. and Ghuysen, J.-M. Characterization of the sporulation-related γ-D-glutamyl-(L)meso-diaminopimelic-acid-hydrolysing peptidase I of Bacillus sphaericus NCTC 9602 as a member of the metallo(zinc) carboxypeptidase A family. Modular design of the protein. Biochem. J. 292 (1993) 563–570. [PMID: 8503890]
[EC 3.4.19.11 created 1996]
 
 
EC 3.4.19.12     
Accepted name: ubiquitinyl hydrolase 1
Reaction: Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal)
Other name(s): ubiquitin C-terminal hydrolase; yeast ubiquitin hydrolase
Comments: Links to polypeptides smaller than 60 residues are hydrolysed more readily than those to larger polypeptides. Isoforms exist with quantitatively different specificities, amongst the best known being UCH-L1 and UCH-L3, which are major proteins of the brain of mammals [1]. Inhibited by ubiquitin aldehyde (in which Gly76 is replaced by aminoacetaldehyde). Ubiquitinyl hydrolase 1 is the type example of peptidase family C12, with a similar protein fold to papain and catalytic amino acids Cys, His and Asp. There is a separate family (C19) of enzymes that also hydrolyse ubiquitinyl bonds, and it is thought that all the ubiquitinyl hydrolases are also ubiquitin thiolesterases (EC 3.1.2.15)
References:
1.  Johnston, S.C., Larsen, C.N., Cook, W.J., Wilkinson, K.D. and Hill, C.P. Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8Å resolution. EMBO J. 16 (1997) 3787–3796. [PMID: 9233788]
2.  Wilkinson, K.D. Ubiquitin C-terminal hydrolase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 470–472.
[EC 3.4.19.12 created 2000]
 
 
EC 3.4.19.13     
Accepted name: glutathione hydrolase
Reaction: glutathione + H2O = L-cysteinylglycine + L-glutamate
Other name(s): glutathionase; GGT (ambiguous); γ-glutamyltranspeptidase (ambiguous)
Comments: This protein also has EC 2.3.2.2 (γ-glutamyltransferase) activity. The enzyme consists of two chains that are created by the proteolytic cleavage of a single precursor polypeptide. The N-terminal L-threonine of the C-terminal subunit functions as the active site for both the cleavage and the hydrolysis reactions [2-5]. The human enzyme also hydrolyses oxidized glutathione and leukotriene C4 with similar efficiency, while the mouse enzyme does not [6-7].
References:
1.  Hanigan, M.H. and Ricketts, W.A. Extracellular glutathione is a source of cysteine for cells that express γ-glutamyl transpeptidase. Biochemistry 32 (1993) 6302–6306. [PMID: 8099811]
2.  Suzuki, H. and Kumagai, H. Autocatalytic processing of γ-glutamyltranspeptidase. J. Biol. Chem. 277 (2002) 43536–43543. [PMID: 12207027]
3.  Okada, T., Suzuki, H., Wada, K., Kumagai, H. and Fukuyama, K. Crystal structures of γ-glutamyltranspeptidase from Escherichia coli, a key enzyme in glutathione metabolism, and its reaction intermediate. Proc. Natl. Acad. Sci. USA 103 (2006) 6471–6476. [PMID: 16618936]
4.  Boanca, G., Sand, A., Okada, T., Suzuki, H., Kumagai, H., Fukuyama, K. and Barycki, J.J. Autoprocessing of Helicobacter pylori γ-glutamyltranspeptidase leads to the formation of a threonine-threonine catalytic dyad. J. Biol. Chem. 282 (2007) 534–541. [PMID: 17107958]
5.  Okada, T., Suzuki, H., Wada, K., Kumagai, H. and Fukuyama, K. Crystal structure of the γ-glutamyltranspeptidase precursor protein from Escherichia coli. Structural changes upon autocatalytic processing and implications for the maturation mechanism. J. Biol. Chem. 282 (2007) 2433–2439. [PMID: 17135273]
6.  Wickham, S., West, M.B., Cook, P.F. and Hanigan, M.H. Gamma-glutamyl compounds: substrate specificity of γ-glutamyl transpeptidase enzymes. Anal. Biochem. 414 (2011) 208–214. [PMID: 21447318]
7.  Carter, B.Z., Wiseman, A.L., Orkiszewski, R., Ballard, K.D., Ou, C.N. and Lieberman, M.W. Metabolism of leukotriene C4 in γ-glutamyl transpeptidase-deficient mice. J. Biol. Chem. 272 (1997) 12305–12310. [PMID: 9139674]
[EC 3.4.19.13 created 2011]
 
 
EC 3.4.19.14     
Accepted name: leukotriene-C4 hydrolase
Reaction: leukotriene C4 + H2O = leukotriene D4 + L-glutamate
Other name(s): γ-glutamyl leukotrienase; GGT5
Comments: The mouse enzyme is specific for leukotriene C4, while the human enzyme also has considerable activity towards glutathione and oxidized glutathione (cf. EC 3.4.19.13, glutathione hydrolase) [3-4].
References:
1.  Carter, B.Z., Wiseman, A.L., Orkiszewski, R., Ballard, K.D., Ou, C.N. and Lieberman, M.W. Metabolism of leukotriene C4 in γ-glutamyl transpeptidase-deficient mice. J. Biol. Chem. 272 (1997) 12305–12310. [PMID: 9139674]
2.  Shi, Z.Z., Han, B., Habib, G.M., Matzuk, M.M. and Lieberman, M.W. Disruption of γ-glutamyl leukotrienase results in disruption of leukotriene D4 synthesis in vivo and attenuation of the acute inflammatory response. Mol. Cell Biol. 21 (2001) 5389–5395. [PMID: 11463821]
3.  Han, B., Luo, G., Shi, Z.Z., Barrios, R., Atwood, D., Liu, W., Habib, G.M., Sifers, R.N., Corry, D.B. and Lieberman, M.W. γ-glutamyl leukotrienase, a novel endothelial membrane protein, is specifically responsible for leukotriene D4 formation in vivo. Am J Pathol 161 (2002) 481–490. [PMID: 12163373]
4.  Wickham, S., West, M.B., Cook, P.F. and Hanigan, M.H. Gamma-glutamyl compounds: substrate specificity of γ-glutamyl transpeptidase enzymes. Anal. Biochem. 414 (2011) 208–214. [PMID: 21447318]
[EC 3.4.19.14 created 2012]
 
 
EC 3.4.19.15     
Accepted name: desampylase
Reaction: an N6-[small archaeal modifier protein]-[protein]-L-lysine + H2O = a [protein]-L-lysine + a small archaeal modifier protein
Glossary: SAMP = small archaeal modifier protein
Other name(s): SAMP-protein conjugate cleaving protease; HvJAMM1
Systematic name: N6-[small archaeal modifier protein]-[protein]-L-lysine hydrolase
Comments: The enzyme, characterized from the archaeon Haloferax volcanii, specifically cleaves the ubiquitin-like small modifier proteins SAMP1 and SAMP2 from protein conjugates, hydrolysing the isopeptide bond between a lysine residue of the target protein and the C-terminal glycine of the modifier protein. The enzyme contains Zn2+. cf. EC 3.4.19.12, ubiquitinyl hydrolase 1. In peptidase family M67.
References:
1.  Hepowit, N.L., Uthandi, S., Miranda, H.V., Toniutti, M., Prunetti, L., Olivarez, O., De Vera, I.M., Fanucci, G.E., Chen, S. and Maupin-Furlow, J.A. Archaeal JAB1/MPN/MOV34 metalloenzyme (HvJAMM1) cleaves ubiquitin-like small archaeal modifier proteins (SAMPs) from protein-conjugates. Mol. Microbiol. 86 (2012) 971–987. [PMID: 22970855]
[EC 3.4.19.15 created 2015 as EC 3.4.24.88, transferred 2016 to EC 3.4.19.15]
 
 
EC 3.4.19.16     
Accepted name: glucosinolate γ-glutamyl hydrolase
Reaction: (1) an (E)-1-(glutathion-S-yl)-N-hydroxy-ω-(methylsulfanyl)alkan-1-imine + H2O = an (E)-1-(L-cysteinylglycin-S-yl)-N-hydroxy-ω-(methylsulfanyl)alkan-1-imine + L-glutamate
(2) (E)-1-(glutathion-S-yl)-N-hydroxy-2-(1H-indol-3-yl)ethan-1-imine + H2O = (E)-1-(L-cysteinylglycin-S-yl)-N-hydroxy-2-(1H-indol-3-yl)ethan-1-imine + L-glutamate
(3) (glutathion-S-yl)(1H-indol-3-yl)acetonitrile + H2O = (L-cysteinylglycin-S-yl)(1H-indol-3-yl)acetonitrile + L-glutamate
(4) (Z)-1-(glutathion-S-yl)-N-hydroxy-2-phenylethan-1-imine + H2O = (Z)-1-(L-cysteinyglycin-S-yl)-N-hydroxy-2-phenylethan-1-imine + L-glutamate
Other name(s): GGP1 (gene name); GGP3 (gene name)
Comments: This enzyme, characterized from the plant Arabidopsis thaliana, participates in the biosynthesis of the plant defense compounds glucosinolates and camalexin. It is the only known plant enzyme capable of hydrolysing the γ-glutamyl residue of glutathione in the cytosol.
References:
1.  Geu-Flores, F., Møldrup, M.E., Böttcher, C., Olsen, C.E., Scheel, D. and Halkier, B.A. Cytosolic γ-glutamyl peptidases process glutathione conjugates in the biosynthesis of glucosinolates and camalexin in Arabidopsis. Plant Cell 23 (2011) 2456–2469. [PMID: 21712415]
[EC 3.4.19.16 created 2017]
 
 
EC 3.4.21.1     
Accepted name: chymotrypsin
Reaction: Preferential cleavage: Tyr┼, Trp┼, Phe┼, Leu┼
Other name(s): chymotrypsins A and B; α-chymar ophth; avazyme; chymar; chymotest; enzeon; quimar; quimotrase; α-chymar; α-chymotrypsin A; α-chymotrypsin
Comments: Chymotrypsin A is formed from cattle and pig chymotrypsinogen A, several iso-forms being produced according to the number of bonds hydrolysed in the precursor. Chymotrypsin B (formerly listed as EC 3.4.4.6), formed from chymotrypsinogen B, is homologous with chymotrypsin A. Enzymes with specificity similar to that of chymotrypsins A and B have been isolated from many species. In peptidase family S1 (trypsin family)
References:
1.  Wilcox, P.E. Chymotrypsinogens - chymotrypsins. Methods Enzymol. 19 (1970) 64–108.
2.  Blow, D.M. Structure and mechanism of chymotrypsin. Acc. Chem. Res. 9 (1976) 145–152.
3.  Bauer, C.-A. Active centers of α-chymotrypsin and of Streptomyces griseus proteases 1 and 3. Eur. J. Biochem. 105 (1980) 565–570. [PMID: 6768556]
4.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
5.  Tomita, N., Izumoto, Y., Horii, A., Doi, S., Yokouchi, H., Ogawa, M., Mori, T. and Matsubara, K. Molecular cloning and nucleotide sequence of human pancreatic prechymotrypsinogen cDNA. Biochem. Biophys. Res. Commun. 158 (1989) 569–575. [PMID: 2917002]
[EC 3.4.21.1 created 1961 as EC 3.4.4.5 and EC 3.4.4.6, transferred 1972 to EC 3.4.21.1]
 
 
EC 3.4.21.2     
Accepted name: chymotrypsin C
Reaction: Preferential cleavage: Leu┼, Tyr┼, Phe┼, Met┼, Trp┼, Gln┼, Asn┼
Comments: Formed from pig chymotrypsinogen C, and from cattle subunit II of procarboxypeptidase A. Reacts more readily with Tos-Leu-CH2Cl than Tos-Phe-CH2Cl in contrast to chymotrypsin. In peptidase family S1 (trypsin family)
References:
1.  Peanasky, R.J., Gratecos, D., Baratti, J. and Rovery, M. Mode of activation and N-terminal sequence of subunit II in bovine procarboxypeptidase A and of porcine chymotrypsinogen C. Biochim. Biophys. Acta 181 (1969) 82–92. [PMID: 5792601]
2.  Folk, J.E. Chymotrypsin C (porcine pancreas). Methods Enzymol. 19 (1970) 109–112.
3.  Wilcox, P.E. Chymotrypsinogens - chymotrypsins. Methods Enzymol. 19 (1970) 64–108.
[EC 3.4.21.2 created 1972]
 
 
EC 3.4.21.3     
Accepted name: metridin
Reaction: Preferential cleavage: Tyr┼, Phe┼, Leu┼
little action on Trp-┼
Other name(s): Metridium proteinase A; sea anemone protease A; sea anemone proteinase A
Comments: Digestive enzyme from the sea anemone Metridium senile.
References:
1.  Gibson, D. and Dixon, G.H. Chymotrypsin-like proteases from the sea anemone, Metridium senile. Nature 222 (1969) 753–756. [PMID: 4389140]
2.  Stevenson, K.J., Gibson, D. and Dixon, G.H. Amino acid analyses of chymotrysin-like proteases from the sea anemone (Metridium senile). Can. J. Biochem. 52 (1974) 93–100. [PMID: 4150616]
[EC 3.4.21.3 created 1972]
 
 
EC 3.4.21.4     
Accepted name: trypsin
Reaction: Preferential cleavage: Arg┼, Lys┼
Other name(s): α-trypsin; β-trypsin; cocoonase; parenzyme; parenzymol; tryptar; trypure; pseudotrypsin; tryptase; tripcellim; sperm receptor hydrolase
Comments: The single polypeptide chain cattle β-trypsin is formed from trypsinogen by cleavage of one peptide bond. Further peptide bond cleavages produce α and other iso-forms. Isolated as multiple cationic and anionic trypsins [5] from the pancreas of many vertebrates and from lower species including crayfish, insects (cocoonase) and microorganisms (Streptomyces griseus) [3]. Type example of peptidase family S1.
References:
1.  Huber, R. and Bode, W. Structural basis of the activation and action of trypsin. Acc. Chem. Res. 11 (1978) 114–122.
2.  Walsh, K.A. Trypsinogens and trypsins of various species. Methods Enzymol. 19 (1970) 41–63.
3.  Read, R.J., Brayer, G.D., Jurásek, L. and James, M.N.G. Critical evaluation of comparative model building of Streptomyces griseus trypsin. Biochemistry 23 (1984) 6570–6575. [PMID: 6442164]
4.  Fiedler, F. Effects of secondary interactions on the kinetics of peptide and peptide ester hydrolysis by tissue kallikrein and trypsin. Eur. J. Biochem. 163 (1987) 303–312. [PMID: 3643848]
5.  Fletcher, T.S., Alhadeff, M., Craik, C.S. and Largman, C. Isolation and characterization of a cDNA encoding rat cationic trypsinogen. Biochemistry 26 (1987) 3081–3086. [PMID: 3112218]
6.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
7.  Tani, T., Kawashima, I., Mita, K. and Takiguchi, Y. Nucleotide sequence of the human pancreatic trypsinogen III cDNA. Nucleic Acids Res. 18 (1990) 1631. [PMID: 2326201]
[EC 3.4.21.4 created 1961 as EC 3.4.4.4, transferred 1972 to EC 3.4.21.4]
 
 
EC 3.4.21.5     
Accepted name: thrombin
Reaction: Selective cleavage of Arg┼Gly bonds in fibrinogen to form fibrin and release fibrinopeptides A and B
Other name(s): fibrinogenase; thrombase; thrombofort; topical; thrombin-C; tropostasin; activated blood-coagulation factor II; blood-coagulation factor IIa; factor IIa; E thrombin; β-thrombin; γ-thrombin
Comments: Formed from prothrombin. More selective than trypsin and plasmin. In peptidase family S1 (trypsin family).
References:
1.  Baughman, D.J. Thrombin assay. Methods Enzymol. 19 (1970) 145–157.
2.  Magnusson, S. Bovine prothrombin and thrombin. Methods Enzymol. 19 (1970) 157–184.
3.  Miller, K.D. Horse prothrombin. Methods Enzymol. 19 (1970) 140–145.
4.  Lundblad, R.L., Kingdon, H.S. and Mann, K.G. Thrombin. Methods Enzymol. 45 (1976) 156–176. [PMID: 1011989]
5.  Mann, K.G. Prothrombin. Methods Enzymol. 45 (1976) 123–156. [PMID: 1011988]
6.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
7.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
8.  MacGillivray, R.T.A. and Davie, E.W. Characterization of bovine prothrombin mRNA and its translation product. Biochemistry 23 (1984) 1626–1634. [PMID: 6326805]
[EC 3.4.21.5 created 1961 as EC 3.4.4.13, transferred 1972 to EC 3.4.21.5]
 
 
EC 3.4.21.6     
Accepted name: coagulation factor Xa
Reaction: Selective cleavage of Arg┼Thr and then Arg┼Ile bonds in prothrombin to form thrombin
Other name(s): thrombokinase; prothrombase; prothrombinase; activated blood-coagulation factor X; autoprothrombin C; thromboplastin; plasma thromboplastin; factor Xa; activated Stuart-Prower factor; activated factor X
Comments: A blood coagulation factor formed from the proenzyme factor X by limited proteolysis. Factor X is a glycoprotein composed of a heavy chain and a light chain, which are generated from a precursor protein by the excision of the tripeptide RKR and held together by one or more disulfide bonds. The activated factor Xa converts prothrombin to thrombin in the presence of factor Va, Ca2+ and phospholipids. Scutelarin (EC 3.4.21.60) has similar specificity, but does not require factor Va.
References:
1.  Fujikawa, K. and Davie, E.W. Bovine factor X (Stuart factor). Methods Enzymol. 45 (1976) 89–95. [PMID: 1012041]
2.  Jesty, J. and Nemerson, Y. The activation of bovine coagulation factor X. Methods Enzymol. 45 (1976) 95–107. [PMID: 1012042]
3.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
4.  Jackson, C.M. and Nemerson, Y. Blood coagulation. Annu. Rev. Biochem. 49 (1980) 765–811. [PMID: 6996572]
5.  McMullen, B.A., Fujikawa, K., Kisiel, W., Sasagawa, T., Howald, W.N., Kwa, E.Y. and Weinstein, B. Complete amino acid sequence of the light chain of human blood coagulation factor X: evidence for identification of residue 63 as β-hydroxyaspartic acid. Biochemistry 22 (1983) 2875–2884. [PMID: 6871167]
6.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
[EC 3.4.21.6 created 1972, modified 2011]
 
 
EC 3.4.21.7     
Accepted name: plasmin
Reaction: Preferential cleavage: Lys┼ > Arg┼
higher selectivity than trypsin. Converts fibrin into soluble products
Other name(s): fibrinase; fibrinolysin; actase; serum tryptase; thrombolysin
Comments: Formed from plasminogen by proteolysis which results in multiple forms of the active plasmin. In peptidase family S1 (trypsin family).
References:
1.  Castellino, F.J. and Sodetz, J.M. Rabbit plasminogen and plasmin isozymes. Methods Enzymol. 45 (1976) 273–286. [PMID: 138065]
2.  Castellino, F.J. and Powell, J.R. Human plasminogen. Methods Enzymol. 80 (1981) 365–378. [PMID: 6210827]
3.  Robbins, K.C., Summaria, L. and Wohl, R.C. Human plasmin. Methods Enzymol. 80 (1981) 379–387. [PMID: 6210828]
[EC 3.4.21.7 created 1961 as EC 3.4.4.14, transferred 1972 to EC 3.4.21.7]
 
 
EC 3.4.21.8      
Transferred entry: kallikrein. Now EC 3.4.21.34 (plasma kallikrein) and EC 3.4.21.35 (tissue kallikrein)
[EC 3.4.21.8 created 1972, deleted 1981]
 
 
EC 3.4.21.9     
Accepted name: enteropeptidase
Reaction: Activation of trypsinogen by selective cleavage of Lys6┼Ile bond
Other name(s): enterokinase
Comments: Is not inhibited by protein inhibitors of trypsin. In peptidase family S1 (trypsin family).
References:
1.  Light, A. and Janska, H. Enterokinase (enteropeptidase): comparative aspects. Trends Biochem. Sci. 14 (1989) 110–112. [PMID: 2658218]
[EC 3.4.21.9 created 1961 as EC 3.4.4.8, transferred 1972 to EC 3.4.21.9]
 
 
EC 3.4.21.10     
Accepted name: acrosin
Reaction: Preferential cleavage: Arg┼, Lys┼
Other name(s): acrosomal proteinase; acrozonase; α-acrosin; β-acrosin; upsilon-acrosin; acrosomal protease; acrosin amidase
Comments: Occurs in spermatozoa; formed from proacrosin by limited proteolysis. Inhibited by naturally occurring trypsin inhibitors. In peptidase family S1 (trypsin family)
References:
1.  Müller-Esterl, W. and Fritz, H. Sperm acrosin. Methods Enzymol. 80 (1981) 621–632. [PMID: 7043204]
2.  Skoog, M.T., Mehdi, S., Wiseman, J.S. and Bey, P. The specificity of two proteinases that cleave adjacent to arginine, C 1 esterase and acrosin, for peptide p-nitroanilide substrates. Biochim. Biophys. Acta 996 (1989) 89–94. [PMID: 2500154]
3.  Keime, S., Adham, I.M. and Engel, W. Nucleotide sequence and exon-intron organisation of the human proacrosin gene. Eur. J. Biochem. 190 (1990) 195–200. [PMID: 2114285]
[EC 3.4.21.10 created 1972]
 
 
EC 3.4.21.11      
Transferred entry: elastase. Now EC 3.4.21.37, leukocyte elastase
[EC 3.4.21.11 created 1972, deleted 1981]
 
 
EC 3.4.21.12     
Accepted name: α-lytic endopeptidase
Reaction: Preferential cleavage: Ala┼, Val┼ in bacterial cell walls, elastin and other proteins
Other name(s): myxobacter α-lytic proteinase; α-lytic proteinase; α-lytic protease; Mycobacterium sorangium α-lytic proteinase; Myxobacter 495 α-lytic proteinase; α-lytic proteinase; Myxobacter α-lytic proteinase; Mycobacterium sorangium α-lytic proteinase
Comments: From the myxobacterium Lysobacter enzymogenes. In peptidase family S1 (trypsin family)
References:
1.  Olson, M.O.J., Nagabushan, N., Dzwiniel, M., Smillie, L.B. and Whitaker, D.R. Primary structure of α-lytic protease: a bacterial homologue of the pancreatic serine proteases. Nature 228 (1970) 438–442. [PMID: 5482494]
2.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
3.  Epstein, D.M. and Wensink, P.C. The α-lytic protease gene of Lysobacter enzymogenes. The nucleotide sequence predicts a large prepro-peptide with homology to pro-peptides of other chymotrypsin-like enzymes. J. Biol. Chem. 263 (1988) 16586–16590. [PMID: 3053694]
4.  Bone, R., Frank, D., Kettner, C.A. and Agard, D.A. Structural analysis of specificity: α-lytic protease complexes with analogues of reaction intermediates. Biochemistry 28 (1989) 7600–7609. [PMID: 2611204]
[EC 3.4.21.12 created 1972]
 
 
EC 3.4.21.13      
Transferred entry: Phaseolus proteinase. Now EC 3.4.16.6, carboxypeptidase D
[EC 3.4.21.13 created 1972, deleted 1978]
 
 
EC 3.4.21.14      
Transferred entry: now EC 3.4.21.67 endopeptidase So
[EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, deleted 1992]
 
 
EC 3.4.21.15      
Transferred entry: Aspergillus alkaline proteinase. Now EC 3.4.21.63, oryzin
[EC 3.4.21.15 created 1972, deleted 1978 (transferred to EC 3.4.21.14, deleted 1992)]
 
 
EC 3.4.21.16      
Deleted entry: Alternaria serine proteinase
[EC 3.4.21.16 created 1972, deleted 1992]
 
 
EC 3.4.21.17      
Deleted entry:  Arthrobacter serine proteinase
[EC 3.4.21.17 created 1972, deleted 1978 [transferred to EC 3.4.21.14, deleted 1992]]
 
 
EC 3.4.21.18      
Deleted entry: Tenebrio α-proteinase
[EC 3.4.21.18 created 1972 [EC 3.4.99.24 created 1972, incorporated 1978], deleted 1992]
 
 
EC 3.4.21.19     
Accepted name: glutamyl endopeptidase
Reaction: Preferential cleavage: Glu┼, Asp┼
Other name(s): V8 proteinase; endoproteinase Glu-C; staphylococcal serine proteinase
Comments: From Staphylococcus aureus strain V8. In appropriate buffer the specificity is restricted to Glu┼. In peptidase family S1 (trypsin family)
References:
1.  Drapeau, G.R. Protease from Staphylococcus aureus. Methods Enzymol. 45 (1976) 469–475. [PMID: 1012010]
2.  Drapeau, G.R. The primary structure of staphylococcal protease. Can. J. Biochem. 56 (1978) 534–544. [PMID: 96922]
3.  Carmona, C. and Gray, G.L. Nucleotide sequence of the serine protease gene of Staphylococcus aureus, strain V8. Nucleic Acids Res. 15 (1987) 6757. [PMID: 3306605]
[EC 3.4.21.19 created 1978]
 
 
EC 3.4.21.20     
Accepted name: cathepsin G
Reaction: Specificity similar to chymotrypsin C
Other name(s): chymotrypsin-like proteinase; neutral proteinase
Comments: From azurophil granules of polymorphonuclear leukocytes. In peptidase family S1 (trypsin family)
References:
1.  Barrett, A.J. Cathepsin G. Methods Enzymol. 80 (1981) 561–565. [PMID: 7341917]
2.  Tanaka, T., Minematsu, Y., Reilly, C.F., Travis, J. and Powers, J.C. Human leukocyte cathepsin G. Subsite mapping with 4-nitroanilides, chemical modification, and effect of possible cofactors. Biochemistry 24 (1985) 2040–2047. [PMID: 4016099]
3.  Hohn, P.A., Popescu, N.C., Hanson, R.D., Salvesen, G. and Ley, T.J. Genomic organization and chromosomal localization of the human cathepsin G gene. J. Biol. Chem. 264 (1989) 13412–13419. [PMID: 2569462]
[EC 3.4.21.20 created 1978]
 
 
EC 3.4.21.21     
Accepted name: coagulation factor VIIa
Reaction: Selective cleavage of Arg┼Ile bond in factor X to form factor Xa
Other name(s): blood-coagulation factor VIIa; activated blood coagulation factor VII
Comments: Formed from the precursor factor VII. The cattle enzyme is more readily inhibited by diisopropyl fluorophosphate than the human [1]. In peptidase family S1 (trypsin family)
References:
1.  Nemerson, Y. and Esnouf, M.P. Activation of a proteolytic system by a membrane lipoprotein: mechanism of action of tissue factor. Proc. Natl. Acad. Sci. USA 70 (1973) 310–314. [PMID: 4510277]
2.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
3.  Jackson, C.M. and Nemerson, Y. Blood coagulation. Annu. Rev. Biochem. 49 (1980) 765–811. [PMID: 6996572]
4.  Broze, G.J., Jr. and Majerus, P.W. Human factor VII. Methods Enzymol. 80 (1981) 228–237.
[EC 3.4.21.21 created 1978]
 
 
EC 3.4.21.22     
Accepted name: coagulation factor IXa
Reaction: Selective cleavage of Arg┼Ile bond in factor X to form factor Xa
Other name(s): activated Christmas factor; blood-coagulation factor IXa; activated blood-coagulation factor IX; autoprothrombin II; blood platelet cofactor II; activated blood coagulation factor XI
Comments: A chymotrypsin homologue, and one of the γ-carboxyglutamic acid-containing blood coagulation factors. The proenzyme factor IX is activated by factor XIa. In peptidase family S1 (trypsin family)
References:
1.  Fujikawa, K. and Davie, E.W. Bovine factor IX (Christmas factor). Methods Enzymol. 45 (1976) 74–83. [PMID: 1012029]
2.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
3.  Link, R.P. and Castellino, F.J. Kinetic comparison of bovine blood coagulation factor IXaα and IXaβ towards bovine factor X. Biochemistry 22 (1983) 4033–4041. [PMID: 6412750]
4.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
[EC 3.4.21.22 created 1978]
 
 
EC 3.4.21.23      
Deleted entry:  Vipera russelli proteinase
[EC 3.4.21.23 created 1978, deleted 1992]
 
 
EC 3.4.21.24      
Deleted entry:  red cell neutral endopeptidase
[EC 3.4.21.24 created 1978, deleted 1992]
 
 
EC 3.4.21.25     
Accepted name: cucumisin
Reaction: Hydrolysis of proteins with broad specificity
Other name(s): euphorbain; solanain; hurain; tabernamontanain
Comments: From the sarcocarp of the musk melon (Cucumis melo). In peptidase family S8 (subtilisin family). Other endopeptidases from plants, which are less well characterized but presumably of serine-type, include euphorbain from Euphorbia cerifera [6], solanain from horse-nettle Solanum elaeagnifolium [1], hurain from Hura crepitans [2] and tabernamontanain from Tabernamontana grandiflora [3].
References:
1.  Greenberg, D.M. and Winnick, T. Plant proteases. I. Activation-inhibition reactions. J. Biol. Chem. 135 (1940) 761–773.
2.  Jaffé, W.G. Hurain, a new plant protease from Hura crepitans. J. Biol. Chem. 149 (1943) 1–7.
3.  Jaffé, W.G. A new vegetable proteolytic enzyme of the papain class. Rev. Brasil Biol. 3 (1943) 149–157.
4.  Kaneda, M. and Toninaga, N. Isolation and characterization of a proteinase from the sarcocarp of melon fruit. J. Biochem. (Tokyo) 78 (1975) 1287–1296. [PMID: 5423]
5.  Kaneda, M., Ohmine, H., Yonezawa, H. and Tominaga, N. Amino acid sequence around the reactive site of cucumisin from melon fruit. J. Biochem. (Tokyo) 95 (1984) 825–829. [PMID: 6427203]
6.  Lynn, K.R. and Clevette-Radford, N.A. Two proteases from the latex of Elaeophorbia drupifera. Phytochemistry 24 (1985) 2843–2845.
7.  Kaneda, N., Minematsu, Y., Powers, J.C. and Tominaga, N. Specificity of cucumisin in hydrolysis of peptide thiobenzyl esters. Agric. Biol. Chem. 50 (1986) 1075–1076.
[EC 3.4.21.25 created 1978 (EC 3.4.21.56 created 1972 as EC 3.4.99.7 transferred 1989 to EC 3.4.21.56, deleted 1992; EC 3.4.99.9 created 1972 deleted 1992; EC 3.4.99.21 created 1972 deleted 1992; EC 3.4.99.23 created 1972 deleted 1992; all covered by EC 3.4.21.25)]
 
 
EC 3.4.21.26     
Accepted name: prolyl oligopeptidase
Reaction: Hydrolysis of —Pro┼ and to a lesser extent —Ala┼ in oligopeptides
Other name(s): post-proline cleaving enzyme; proline-specific endopeptidase; post-proline endopeptidase; proline endopeptidase; endoprolylpeptidase; prolyl endopeptidase
Comments: Found in vertebrates, plants and Flavobacterium. Generally cytosolic, commonly activated by thiol compounds. Type example of peptidase family S9.
References:
1.  Walter, R. and Yoshimoto, T. Postproline cleaving enzyme: kinetic studies of size and stereospecificity of its active site. Biochemistry 17 (1978) 4139–4144. [PMID: 708698]
2.  Nomura, K. Specificity of prolyl endopeptidase. FEBS Lett. 209 (1986) 235–237. [PMID: 3539636]
3.  Moriyama, A., Nakanishi, M. and Sasaki, M. Porcine muscle prolyl endopeptidase and its endogenous substrates. J. Biochem. (Tokyo) 104 (1988) 112–117. [PMID: 2851585]
4.  Rennex, D., Hemmings, B.A., Hofsteenge, J. and Stone, S.R. cDNA cloning of porcine brain prolyl endopeptidase and identification of the active-site seryl residue. Biochemistry, 30 (1991) 2195–2203. [PMID: 1900195]
[EC 3.4.21.26 created 1978, modified 1981 (EC 3.4.22.18 created 1981, incorporated 1992)]
 
 
EC 3.4.21.27     
Accepted name: coagulation factor XIa
Reaction: Selective cleavage of Arg┼Ala and Arg┼Val bonds in factor IX to form factor IXa
Other name(s): blood-coagulation factor XIa; activated blood-coagulation factor XI; activated plasma thromboplastin antecedent
Comments: In peptidase family S1 (trypsin family), and one of the γ-carboxyglutamic acid-containing blood coagulation factors. The proenzyme factor XI is activated by factor XIIa
References:
1.  Kurachi, K. and Davie, E.W. Human factor XI (plasma thromboplastin antecedent). Methods Enzymol. 80 (1981) 211–220.
2.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
3.  Fujikawa, K., Chung, D.W., Hendrickson, L.E. and Davie, E.W. Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein. Biochemistry 25 (1986) 2417–2424. [PMID: 3636155]
[EC 3.4.21.27 created 1978]
 
 
EC 3.4.21.28      
Transferred entry: Agkistrodon serine proteinase. Now EC 3.4.21.74, venombin A
[EC 3.4.21.28 created 1978, deleted 1992]
 
 
EC 3.4.21.29      
Transferred entry: Bothrops atrox serine proteinase. Now EC 3.4.21.74, venombin A
[EC 3.4.21.29 created 1978, deleted 1992]
 
 
EC 3.4.21.30      
Transferred entry: Crotalus adamanteus serine proteinase. Now EC 3.4.21.74, venombin A
[EC 3.4.21.30 created 1978, deleted 1992]
 
 
EC 3.4.21.31      
Transferred entry: urokinase. Now EC 3.4.21.73, u-plasminogen activator
[EC 3.4.21.31 created 1972 as EC 3.4.99.26, transferred 1978 to EC 3.4.21.31, deleted 1992]
 
 
EC 3.4.21.32     
Accepted name: brachyurin
Reaction: Hydrolysis of proteins, with broad specificity for peptide bonds. Native collagen is cleaved about 75% of the length of the molecule from the N-terminus. Low activity on small molecule substrates of both trypsin and chymotrypsin
Other name(s): Uca pugilator collagenolytic proteinase; crab protease I; crab protease II
Comments: From hepatopancreas of the fiddler crab, Uca pugilator. In peptidase family S1 (trypsin family). Other serine endopeptidases that degrade collagen, but are not listed separately here, include a second endopeptidase from Uca pugilator [4], digestive enzymes from other decapod crustacea [5,6], and an enzyme from the fungus Entomophthora coronata [1].
References:
1.  Hurion, N., Fromentin, H. and Keil, B. Specificity of the collagenolytic enzyme from the fungus Entomophthora coronata: comparison with the bacterial collagenase from Achromobacter iophagus. Arch. Biochem. Biophys. 192 (1979) 438–445. [PMID: 219780]
2.  Grant, G.A., Eisen, A.Z. and Bradshaw, R.A. Collagenolytic protease from fiddler crab (Uca pugilator). Methods Enzymol. 80 (1981) 722–734.
3.  Welgus, H.G., Grant, G.A., Jeffrey, J.J. and Eisen, A.Z. Substrate specificity of the collagenolytic serine protease from Uca pugilator: studies with collagenous substrates. Biochemistry 21 (1982) 5183–5189. [PMID: 6756469]
4.  Welgus, H.G. and Grant, G.A. Degradation of collagen substrates by a trypsin-like serine protease form the fiddler crab Uca pugilator. Biochemistry 22 (1983) 2228–2233. [PMID: 6305411]
5.  Klimova, O.A., Borukhov, S.I., Solovyeva, N.I., Balaevskaya, T.O. and Strongin, A.Y. The isolation and properties of collagenolytic proteases from crab hepatopancreas. Biochem. Biophys. Res. Commun. 166 (1990) 1411–1420. [PMID: 2154979]
6.  Lu, P.-J., Liu, H.-C. and Tsai, I.-H. The midgut trypsins of shrimp (Penaeus monodon). High efficiency toward native protein substrates including collagens. Biol. Chem. Hoppe-Seyler 371 (1990) 851–859. [PMID: 1963309]
[EC 3.4.21.32 created 1978]
 
 
EC 3.4.21.33      
Deleted entry: Entomophthora collagenolytic proteinase
[EC 3.4.21.33 created 1978, deleted 1992]
 
 
EC 3.4.21.34     
Accepted name: plasma kallikrein
Reaction: Selective cleavage of some Arg┼ and Lys┼ bonds, including Lys┼Arg and Arg┼Ser in (human) kininogen to release bradykinin
Other name(s): serum kallikrein; kininogenin; kallikrein I; kallikrein II; kininogenase; kallikrein; callicrein; glumorin; padreatin; padutin; kallidinogenase; bradykininogenase; panceatic kallikrein; onokrein P; dilminal D; depot-Padutin; urokallikrein; urinary kallikrein
Comments: Formed from plasma prokallikrein (Fletcher factor) by factor XIIa. Activates coagulation factors XII, VII and plasminogen. Selective for Arg > Lys in P1, in small molecule substrates.
References:
1.  Heimark, R.L. and Davie, E.W. Bovine and human plasma prekallikrein. Methods Enzymol. 80 (1981) 157–172. [PMID: 6918767]
2.  McRae, B.J., Kurachi, K., Heimark, R.L., Fujikawa, K., Davie, E.W. and Powers, J.C. Mapping the active sites of bovine thrombin, factor IXa, factor Xa, factor XIa, factor XIIa, plasma kallikrein, and trypsin with amino acid and peptide thioesters: development of new sensitive substrates. Biochemistry 20 (1981) 7196–7206. [PMID: 6976185]
3.  Silverberg, M. and Kaplan, A.P. Prekallikrein. Methods Enzymol. 163 (1988) 85–95. [PMID: 3237096]
4.  Seidah, N.G., Ladenheim, R., Mbikay, M., Hamelin, J., Lutfalla, G., Rougeon, F., Lazure, C. and Chrétien, M. The cDNA structure of rat plasma kallikrein. DNA 8 (1989) 563–574. [PMID: 2598771]
5.  Tsuda, Y., Teno, N., Okada, Y., Wanaka, K., Bohgaki, M., Hijikata-Okunomiya, A., Okamoto, U., Naito, T. and Okamoto, S. Synthesis of tripeptide chloromethyl ketones and examination of their inhibitory effects on plasmin and plasma kallikrein. Chem. Pharm. Bull. 37 (1989) 3108–3111. [PMID: 2534361]
[EC 3.4.21.34 created 1965 as EC 3.4.4.21, transferred 1972 to EC 3.4.21.8, part transferred 1981 to EC 3.4.21.34]
 
 
EC 3.4.21.35     
Accepted name: tissue kallikrein
Reaction: Preferential cleavage of Arg┼ bonds in small molecule substrates. Highly selective action to release kallidin (lysyl-bradykinin) from kininogen involves hydrolysis of Met┼ or Leu┼. The rat enzyme is unusual in liberating bradykinin directly from autologous kininogens by cleavage at two Arg┼ bonds [5]
Other name(s): glandular kallikrein; pancreatic kallikrein; submandibular kallikrein; submaxillary kallikrein; kidney kallikrein; urinary kallikrein; kallikrein; salivary kallikrein; kininogenin; kininogenase; callicrein; glumorin; padreatin; padutin; kallidinogenase; bradykininogenase; depot-padutin; urokallikrein; dilminal D; onokrein P
Comments: Formed from tissue prokallikrein by activation with trypsin. In peptidase family S1 (trypsin family). A large number of tissue kallikrein-related sequences have been reported for rats [16] and mice [7], though fewer seem to exist in other mammals. The few that have been isolated and tested on substrates include mouse γ-renin (EC 3.4.21.54), submandibular proteinase A [2,15], epidermal growth-factor-binding protein, nerve growth factor γ-subunit, rat tonin [3,4,9], submaxillary proteinases A and B [10], T-kininogenase [18], kallikreins k7 and k8 [17] and human prostate-specific antigen (γ-seminoprotein, [6])
References:
1.  Fiedler, F., Fink, E., Tschesche, H. and Fritz, H. Porcine glandular kallikreins. Methods Enzymol. 80 (1981) 493–532. [PMID: 7043199]
2.  Anundi, H., Ronne, H., Peterson, P.A. and Rask, L. Partial amino-acid sequence of the epidermal growth-factor-binding protein. Eur. J. Biochem. 129 (1982) 365–371. [PMID: 6295764]
3.  Pesquero, J.L., Boschcov, P., Oliveira, M.C.F. and Paiva, A.C.M. Effect of substrate size on tonin activity. Biochem. Biophys. Res. Commun. 108 (1982) 1441–1446. [PMID: 6295383]
4.  Gutkowska, J., Corvol, P., Figueiredo, A.F., Inagami, T., Bouhnik, J. and Genest, J. Kinetic studies of rat renin and tonin on purified rat angiotensinogen. Can. J. Biochem. Cell Biol. 62 (1984) 137–142. [PMID: 6097352]
5.  Kato, H., Enjyoji, K., Miyata, T., Hayashi, I., Oh-Ishi, S. and Iwanaga, S. Demonstration of arginyl-bradykinin moiety in rat HMW kininogen: direct evidence for liberation of bradykinin by rat glandular kallikreins. Biochem. Biophys. Res. Commun. 127 (1985) 289–295. [PMID: 3844939]
6.  Akiyama, K., Nakamura, T., Iwanaga, S. and Hara, M. The chymotrypsin-like activity of human prostate-specific antigen, γ-seminoprotein. FEBS Lett. 225 (1987) 168–172. [PMID: 3691800]
7.  Evans, B.A., Drinkwater, C.C. and Richards, R.I. Mouse glandular kallikrein genes. Structure and partial sequence analysis of the kallikrein gene locus. J. Biol. Chem. 262 (1987) 8027–8034. [PMID: 3036794]
8.  Fiedler, F. Effects of secondary interactions on the kinetics of peptide and peptide ester hydrolysis by tissue kallikrein and trypsin. Eur. J. Biochem. 163 (1987) 303–312. [PMID: 3643848]
9.  Fujinaga, M. and James, M.N.G. Rat submaxillary gland serine protease, tonin. Structure solution and refinement at 1.8 Å resolution. J. Mol. Biol. 195 (1987) 373–396. [PMID: 2821276]
10.  Kato, H., Nakanishi, E., Enjyoji, K., Hayashi, I., Oh-ishi, S. and Iwanaga, S. Characterization of serine proteinases isolated from rat submaxillary gland: with special reference to the degradation of rat kininogens by these enzymes. J. Biochem. (Tokyo) 102 (1987) 1389–1404. [PMID: 3482210]
11.  Bailey, G.S. Rat pancreas kallikrein. Methods Enzymol. 163 (1989) 115–128. [PMID: 3237072]
12.  Blaber, M., Isackson, P.J., Marsters, J.C., Jr., Burnier, J.P. and Bradshaw, R.A. Substrate specificities of growth factor associated kallikreins of the mouse submandibular gland. Biochemistry 28 (1988) 7813–7819. [PMID: 2611215]
13.  Chao, J. and Chao, L. Rat urinary kallikrein. Methods Enzymol. 163 (1988) 128–143. [PMID: 3070295]
14.  Geiger, R. and Miska, W. Human tissue kallikrein. Methods Enzymol. 163 (1988) 102–115. [PMID: 2975076]
15.  Bertrand, R., Derancourt, J. and Kassab, R. Selective cleavage at lysine of the 50 kDa-20 kDa connector loop segment of skeletal myosin S-1 by endoproteinase Arg-C. FEBS Lett. 246 (1989) 171–176. [PMID: 2523317]
16.  Wines, D.R., Brady, J.M., Pritchett, D.B., Roberts, J.L. and MacDonald, R.J. Organization and expression of the rat kallikrein gene family. J. Biol. Chem. 264 (1989) 7653–7662. [PMID: 2708383]
17.  Elmoujahed, A., Gutman, N., Brillard, M. and Gauthier, F. Substrate specificity of two kallikrein family gene products isolated from the rat submaxillary gland. FEBS Lett. 265 (1990) 137–140. [PMID: 2194829]
18.  Xiong, W., Chen, L.-M. and Chao, J. Purification and characterization of a kallikrein-like T-kininogenase. J. Biol. Chem. 265 (1990) 2822–2827. [PMID: 2303430]
[EC 3.4.21.35 created 1965 as EC 3.4.4.21, transferred 1972 to EC 3.4.21.8, part transferred 1981 to EC 3.4.21.35]
 
 
EC 3.4.21.36     
Accepted name: pancreatic elastase
Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage: Ala┼
Other name(s): pancreatopeptidase E; pancreatic elastase I; elastase; elaszym; serine elastase
Comments: Formed by activation of proelastase from mammalian pancreas by trypsin. In peptidase family S1 (trypsin family). Formerly included in EC 3.4.21.11
References:
1.  Shotton, D.M. Elastase. Methods Enzymol. 19 (1970) 113–140.
2.  Harper, J.W., Cook, R.R., Roberts, C.J., McLaughlin, B.J. and Powers, J.C. Active site mapping of the serine proteases human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II, bovine chymotrypsin Aα, and Staphylococcus aureus protease V-8 using tripeptide thiobenzyl ester substrates. Biochemistry 23 (1984) 2995–3002. [PMID: 6380580]
3.  Kawashima, I., Tani, T., Shimoda, K. and Takiguchi, Y. Characterization of pancreatic elastase II cDNAs: two elastase II mRNAs are expressed in human pancreas. DNA 6 (1987) 163–172. [PMID: 3646943]
4.  Bieth, J.G., Dirrig, S., Jung, M.-L., Boudier, C., Papamichael, E., Sakarellos, C. and Dimicoli, J.-L. Investigation of the active center of rat pancreatic elastase. Biochim. Biophys. Acta 994 (1989) 64–74. [PMID: 2909256]
5.  Bode, W., Meyer, E., Jr. and Powers, J.C. Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry 28 (1989) 1951–1963. [PMID: 2655701]
[EC 3.4.21.36 created 1981 (EC 3.4.4.7 created 1961, transferred 1972 to EC 3.4.21.11 created 1972, part incorporated 1984)]
 
 
EC 3.4.21.37     
Accepted name: leukocyte elastase
Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage Val┼ > Ala┼
Other name(s): lysosomal elastase; neutrophil elastase; polymorphonuclear leukocyte elastase; elastase; elaszym; serine elastase; lysosomal elastase; granulocyte elastase
Comments: Differs from pancreatic elastase in specificity on synthetic substrates and in inhibitor sensitivity. In peptidase family S1 (trypsin family). Formerly included in EC 3.4.21.11
References:
1.  Barrett, A.J. Leukocyte elastase. Methods Enzymol. 80 (1981) 581–588. [PMID: 7043201]
2.  Harper, J.W., Cook, R.R., Roberts, C.J., McLaughlin, B.J. and Powers, J.C. Active site mapping of the serine proteases human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II, bovine chymotrypsin Aα, and Staphylococcus aureus protease V-8 using tripeptide thiobenzyl ester substrates. Biochemistry 23 (1984) 2995–3002. [PMID: 6380580]
3.  Stein, R.L., Strimpler, A.M., Hori, H. and Powers, J.C. Catalysis by human leukocyte elastase: mechanistic insights into specificity requirements. Biochemistry 26 (1987) 1301–1305. [PMID: 3646070]
4.  Bode, W., Meyer, E., Jr. and Powers, J.C. Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry 28 (1989) 1951–1963. [PMID: 2655701]
[EC 3.4.21.37 created 1981 (EC 3.4.4.7 created 1961, transferred 1972 to EC 3.4.21.11 created 1972, part incorporated 1984)]
 
 
EC 3.4.21.38     
Accepted name: coagulation factor XIIa
Reaction: Selective cleavage of Arg┼Ile bonds in factor VII to form factor VIIa and factor XI to form factor XIa
Other name(s): Hageman factor (activated); blood-coagulation factor XIIf; activated β blood-coagulation factor XII; prealbumin activator; Hageman factor β-fragment; Hageman factor fragment HFf; blood-coagulation factor XIIaβ; prekallikrein activator; kallikreinogen activator
Comments: Also activates plasminogen and plasma prokallikrein. Formed from the proenzyme, factor XII, by plasma kallikrein or factor XIIa. In peptidase family S1 (trypsin family)
References:
1.  Fujikawa, K. and Davie, E.W. Human factor XII (Hageman factor). Methods Enzymol. 80 (1981) 198–211. [PMID: 6918768]
2.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
3.  Que, B.G. and Davie, E.W. Characterization of a cDNA coding for human factor XII (Hageman factor). Biochemistry 25 (1986) 1525–1528. [PMID: 3011063]
4.  Fujikawa, K. Bovine Hageman factor and its fragments. Methods Enzymol. 163 (1988) 54–68. [PMID: 3237089]
5.  Silverberg, M. and Kaplan, A.P. Human Hageman factor and its fragments. Methods Enzymol. 163 (1988) 68–80. [PMID: 3237092]
[EC 3.4.21.38 created 1981]
 
 
EC 3.4.21.39     
Accepted name: chymase
Reaction: Preferential cleavage: Phe┼ > Tyr┼ > Trp┼ > Leu┼
Other name(s): mast cell protease I; skeletal muscle protease; skin chymotryptic proteinase; mast cell serine proteinase, chymase; skeletal muscle (SK) protease
Comments: In mast cell granules. In peptidase family S1 (trypsin family)
References:
1.  Woodbury, R.G., Everitt, M. and Neurath, H. Mast cell proteases. Methods Enzymol. 80 (1981) 588–609. [PMID: 7043202]
2.  Powers, J.C., Tanaka, T., Harper, J.W., Minematsu, Y., Barker, L., Lincoln, D., Crumley, K.V., Fraki, J.E., Schechter, N.M., Lazarus, G.G., Nakajima, K., Nakashino, K., Neurath, H. and Woodbury, R.G. Mammalian chymotrypsin-like enzymes. Comparative reactivities of rat mast cell proteases, human and dog skin chymases, and human cathepsin G with peptide 4-nitroanilide substrates and with peptide chloromethyl ketone and sulfonyl fluoride inhibitors. Biochemistry 24 (1985) 2048–2058. [PMID: 3893542]
3.  Johnson, L.A., Moon, K.E. and Eisenberg, M. Purification to homogeneity of the human skin chymotryptic proteinase "chymase". Anal. Biochem. 155 (1986) 358–364. [PMID: 2425663]
[EC 3.4.21.39 created 1981]
 
 
EC 3.4.21.40      
Deleted entry:  submandibular proteinase A
[EC 3.4.21.40 created 1981, deleted 1992]
 
 
EC 3.4.21.41     
Accepted name: complement subcomponent C1r
Reaction: Selective cleavage of Lys(or Arg)┼Ile bond in complement subcomponent C1s to form C1s (EC 3.4.21.42)
Other name(s): activated complement C1r; C1r esterase; activated complement C1r
Comments: Activated from proenzyme C1r in plasma during activation of the complement system by the "classical" route. In peptidase family S1 (trypsin family)
References:
1.  Sim, R.B. The human complement system serine proteases C1r and C1s and their proenzymes. Methods Enzymol. 80 (1981) 26–42. [PMID: 6281620]
2.  Leytus, S.P., Kurachi, K., Sakariassen, K.S. and Davie, E.W. Nucleotide sequence of the cDNA coding for human complement C1r. Biochemistry 25 (1986) 4855–4863. [PMID: 3021205]
3.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [PMID: 3052276]
[EC 3.4.21.41 created 1981]
 
 
EC 3.4.21.42     
Accepted name: complement subcomponent C1s
Reaction: Cleavage of Arg┼Ala bond in complement component C4 to form C4a and C4b, and Lys(or Arg)┼Lys bond in complement component C2 to form C2a and C2b: the "classical" pathway C3 convertase
Other name(s): C1 esterase; activated complement C1s; complement C1r
Comments: Activated from proenzyme C1s in plasma by complement subcomponent C1r. In peptidase family S1 (trypsin family)
References:
1.  Sim, R.B. The human complement system serine proteases C1r and C1s and their proenzymes. Methods Enzymol. 80 (1981) 26–42. [PMID: 6281620]
2.  MacKinnon, C.M., Carter, P.E., Smyth, S.J., Dunbar, B. and Fothergill, J.E. Molecular cloning of cDNA for human complement component C1s. The complete amino acid sequence. Eur. J. Biochem. 169 (1987) 547–553. [PMID: 3500856]
3.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [PMID: 3052276]
4.  Skoog, M.T., Mehdi, S., Wiseman, J.S. and Bey, P. The specificity of two proteinases that cleave adjacent to arginine, C 1 esterase and acrosin, for peptide p-nitroanilide substrates. Biochim. Biophys. Acta 996 (1989) 89–94. [PMID: 2500154]
[EC 3.4.21.42 created 1981]
 
 
EC 3.4.21.43     
Accepted name: classical-complement-pathway C3/C5 convertase
Reaction: Selective cleavage of Arg┼Ser bond in complement component C3 α-chain to form C3a and C3b, and Arg┼ bond in complement component C5 α-chain to form C5a and C5b
Other name(s): C3 convertase; C42; C4b,2a; C5 convertase; C423; C4b,2a,3b; C42; C5 convertase; C423; C4b,2a,3b; complement C.hivin.4.hivin2; complement C3 convertase
Comments: A complex of complement fragments C4b, C2a and C2b. C2a contains the active site, C2b the site for C4b binding. C2a and C2b are formed by cleavage of proenzyme C2 by complement subcomponent C1s. Cleavage of C5 requires complement fragment C3b which binds C5 and renders it susceptible to cleavage by the C4b,2a complex. Includes former EC 3.4.21.44. Complement component C2a is in peptidase family S1 (trypsin family)
References:
1.  Kerr, M.A. The second component of human complement. Methods Enzymol. 80 (1980) 54–64.
2.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [PMID: 3052276]
[EC 3.4.21.43 created 1981 (EC 3.4.21.44 created 1981, incorporated 1984)]
 
 
EC 3.4.21.44      
Transferred entry: complement component C5 convertase. Now EC 3.4.21.43, classical-complement-pathway C3/C5 convertase
[EC 3.4.21.44 created 1981, deleted 1984]
 
 
EC 3.4.21.45     
Accepted name: complement factor I
Reaction: Inactivates complement subcomponents C3b, iC3b and C4b by proteolytic cleavage
Other name(s): complement component C3b inactivator; C3b inactivator; C3b/C4b inactivator; C3bINA; complement C3b/C4b inactivator; complement C4b inactivator; conglutinogen-activating factor C; complement C3b inactivator; factor I; complement C4bi
Comments: Cleavage of complement subcomponent C3b requires its binding to cofactor factor H or complement receptor CR1; cleavage of iC3b requires complement receptor CR1; cleavage of C4b requires C4b-binding protein. In peptidase family S1 (trypsin family)
References:
1.  Nagasawa, S., Ichihara, C. and Stroud, R.M. Cleavage of C4b by C3b inactivator: production of a nicked form from C4b, C4b', as an intermediate cleavage product of C4b by C3b inactivator. J. Immunol. 125 (1980) 578–582. [PMID: 7391570]
2.  Crossley, L.G. C3b inactivator and β1H. Methods Enzymol. 80 (1981) 112–124. [PMID: 6210825]
3.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [PMID: 3052276]
[EC 3.4.21.45 created 1981]
 
 
EC 3.4.21.46     
Accepted name: complement factor D
Reaction: Selective cleavage of Arg┼Lys bond in complement factor B when in complex with complement subcomponent C3b or with cobra venom factor
Other name(s): C3 proactivator convertase; properdin factor D esterase; factor D; factor D (complement)
Comments: A component of the alternative pathway of complement activation. This reaction is analogous to the activation of complement component C2 by complement subcomponent C1s. In peptidase family S1 (trypsin family)
References:
1.  Reid, K.B.M., Johnson, D.M.A., Gagnon, J. and Prohaska, R. Preparation of human factor D of the alternative pathway of complement. Methods Enzymol. 80 (1981) 134–143. [PMID: 6918766]
2.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [PMID: 3052276]
[EC 3.4.21.46 created 1981]
 
 
EC 3.4.21.47     
Accepted name: alternative-complement-pathway C3/C5 convertase
Reaction: Cleavage of Arg┼Ser bond in complement component C3 α-chain to yield C3a and C3b, and Arg┼ bond in complement component C5 α-chain to yield C5a and C5b
Other name(s): complement component C3/C5 convertase (alternative); proenzyme factor B; properdin factor B; C3 proactivator; glycine-rich β-glycoprotein; heat-labile factor; C3 convertase; C3b,Bb,CVF,Bb,C5 convertase; (C3b)n,Bb; complement C 3(C 5) convertase (amplification); alternative complement pathway C3(C5) convertase; C5 convertase; CVF,Bb; (CVF)-dependent glycine-rich-β-glucoprotein; cobra venom factor-dependent C3 convertase
Comments: A bimolecular complex of complement fragment Bb with either C3b or cobra venom factor; Bb contains the active site. Bb is formed by cleavage of proenzyme factor B by factor D. Cleavage of complement component C5 requires additional C3b which binds C5 and renders it susceptible to cleavage by C3b,Bb complex. C3b,Bb is stabilized in plasma by factor P. Complement factor B is in peptidase family S1 (trypsin family)
References:
1.  Kerr, M.A. Human factor B. Methods Enzymol. 80 (1981) 102–112. [PMID: 7043188]
2.  Morley, B.J. and Campbell, R.D. Internal homologies of the Ba fragment from human complement component Factor B, as a class III MHC antigen. EMBO J. 3 (1984) 153–157. [PMID: 6323161]
3.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [PMID: 3052276]
[EC 3.4.21.47 created 1981]
 
 
EC 3.4.21.48     
Accepted name: cerevisin
Reaction: Hydrolysis of proteins with broad specificity, and of Bz-Arg-OEt Ac-Tyr-OEt. Does not hydrolyse peptide amides
Other name(s): yeast proteinase B; proteinase yscB; baker’s yeast proteinase B; brewer’s yeast proteinase; peptidase β
Comments: From Saccharomyces cerevisiae (baker’s yeast, brewer’s yeast). In peptidase family S8 (subtilisin family), but contains a Cys residue near the active site His, and is inhibited by mercurials. Proteinase ycaB is a similar enzyme from the yeast Candida albicans [3]
References:
1.  Félix, F. and Brouillet, N. Purification et proprietes de deux peptidases de levure de brasserie. Biochim. Biophys. Acta 122 (1966) 127–144. [PMID: 4961236]
2.  Kominami, E., Hoffschulte, H., Leuschel, L., Maier, K. and Holzer, H. The substrate specificity of proteinase B from baker’s yeast. Biochim. Biophys. Acta 661 (1981) 136–141. [PMID: 7028121]
3.  Farley, P.C., Shepherd, M.G. and Sullivan, P.A. The purification and properties of yeast proteinase B from Candida albicans. Biochem. J. 236 (1986) 177–184. [PMID: 3539100]
4.  Moehle, C.M., Tizard, R., Lemmon, S.K., Smart, J. and Jones, E.W. Protease B of the lysosome like vacuole of the yeast Saccharomyces cerevisiae is homologous to the subtilisin family of serine proteases. Mol. Cell. Biol. 7 (1987) 4390–4399. [PMID: 3325823]
[EC 3.4.21.48 created 1972 as EC 3.4.22.9, transferred 1981 to EC 3.4.21.48]
 
 
EC 3.4.21.49     
Accepted name: hypodermin C
Reaction: Hydrolysis of proteins including native collagen at ┼Ala bond leaving an N-terminal (75%) and a C-terminal (25%) fragment
Other name(s): Hypoderma collagenase
Comments: From the larva of a warble fly, Hypoderma lineatum. Little action on small molecule substrates of trypsin, chymotrypsin, elastase or microbial collagenases. In peptidase family S1 (trypsin family)
References:
1.  Lecroisey, A., Boulard, C. and Keil, B. Chemical and enzymatic characterization of the collagenase from the insect Hypoderma lineatum. Eur. J. Biochem. 101 (1979) 385–393. [PMID: 230030]
2.  Lecroisey, A. and Keil, B. Specificity of the collagenase from the insect Hypoderma lineatum. Eur. J. Biochem. 152 (1985) 123–130. [PMID: 2995028]
3.  Lecroisey, A., Gilles, A.-M., De Wolf, A. and Keil, B. Complete amino acid sequence of the collagenase from the insect Hypoderma lineatum. J. Biol. Chem. 262 (1987) 7546–7551. [PMID: 3034899]
[EC 3.4.21.49 created 1981]
 
 
EC 3.4.21.50     
Accepted name: lysyl endopeptidase
Reaction: Preferential cleavage: Lys┼, including -Lys┼Pro-
Other name(s): Achromobacter proteinase I (also see Comment); Achromobacter lyticus alkaline proteinase I; protease I; achromopeptidase; lysyl bond specific proteinase
Comments: From Achromobacter lyticus [6]. Enzymes with similar specificity are produced by Lysobacter enzymogenes (Endoproteinase Lys-C; [3]) and Pseudomonas aeruginosa (Ps-1; [4]). In peptidase family S1 (trypsin family)
References:
1.  Masaki, T., Tanabe, M., Nakamura, K. and Soejima, M. Studies on a new proteolytic enzyme from Achromobacter lyticus M497-1. I. Purification and some enzymatic properties. Biochim. Biophys. Acta. 660 (1981) 44–50. [PMID: 6791693]
2.  Masaki, T., Fujihasi, T., Nakamura, K. and Soejima, M. Studies on a new proteolytic enzyme from Achromobacter lyticus M497-1. II. Specificity and inhibition studies of Achromobacter protease I. Biochim. Biophys. Acta 660 (1981) 51–55. [PMID: 6168293]
3.  Jekel, P.A., Weijer, W.J. and Beintema, J.J. Use of endoproteinase Lys-C from Lysobacter enzymogenes in protein sequence analysis. Anal. Biochem. 134 (1983) 347–354. [PMID: 6359954]
4.  Elliott, B.W. and Cohen, C. Isolation and characterization of a lysine-specific protease from Pseudomonas aeruginosa. J. Biol. Chem. 261 (1986) 11259–11265. [PMID: 3090046]
5.  Ohara, T., Makino, K., Shinagawa, H., Nakata, A., Norioka, S. and Sakiyama, F. Cloning, nucleotide sequence, and expression of Achromobacter protease I gene. J. Biol. Chem. 264 (1989) 20625. [PMID: 2684982]
6.  Tsunasawa, S., Masaki, T., Hirose, M., Soejima, M. and Sakiyama, F. The primary structure and structural characteristics of Achromobacter lyticus protease I, a lysine-specific serine protease. J. Biol. Chem. 264 (1989) 3832–3839. [PMID: 2492988]
[EC 3.4.21.50 created 1983]
 
 
EC 3.4.21.51      
Deleted entry:  Leukocyte-membrane neutral endopeptidase
[EC 3.4.21.51 created 1984, deleted 1992]
 
 
EC 3.4.21.52      
Deleted entry:  Cathepsin R
[EC 3.4.21.52 created 1981 as EC 3.4.99.33, transferred 1984 to EC 3.4.21.52, deleted 1992]
 
 
EC 3.4.21.53     
Accepted name: endopeptidase La
Reaction: Hydrolysis of proteins in presence of ATP
Other name(s): ATP-dependent serine proteinase; lon proteinase; protease La; proteinase La; ATP-dependent lon proteinase; ATP-dependent protease La; Escherichia coli proteinase La; Escherichia coli serine proteinase La; gene lon protease; gene lon proteins; PIM1 protease; PIM1 proteinase; serine protease La
Comments: Product of the lon gene in Escherichia coli. ATP hydrolysis is linked with peptide bond hydrolysis; vanadate inhibits both reactions. Type example of peptidase family S16. A similar enzyme occurs in animal mitochondria
References:
1.  Desautels, M. and Goldberg, A.L. Demonstration of an ATP-dependent, vanadate-sensitive endoprotease in the matrix of rat liver mitochondria. J. Biol. Chem. 257 (1982) 11673–11679. [PMID: 6749845]
2.  Larimore, F.S., Waxman, L. and Goldberg, A.L. Studies of the ATP-dependent proteolytic enzyme, protease La, from Escherichia coli. J. Biol. Chem. 257 (1982) 4187–4195. [PMID: 7040380]
3.  Chin, D.T., Goff, S.A., Webster, T., Smith, T. and Goldberg, A.L. Sequence of the lon gene in Escherichia coli. A heat-shock gene which encodes the ATP-dependent protease La. J. Biol. Chem. 263 (1988) 11718–11728. [PMID: 3042779]
[EC 3.4.21.53 created 1986]
 
 
EC 3.4.21.54     
Accepted name: γ-renin
Reaction: Cleavage of the Leu┼Leu bond in synthetic tetradecapeptide renin substrate (horse), to produce angiotensin I, but not active on natural angiotensinogen, unlike renin (EC 3.4.23.15). Also hydrolyses Bz-Arg-p-nitroanilide
Comments: A member of the tissue kallikrein family, from submandibular glands of male mice. In peptidase family S1 (trypsin family)
References:
1.  Poe, M., Wu, J.K., Florance, J.R., Rodkey, J.A., Bennett, C.D. and Hoogsteen, K. Purification and properties of renin and γ-renin from the mouse submaxillary gland. J. Biol. Chem. 258 (1983) 2209–2216. [PMID: 6337154]
2.  Drinkwater, C.C., Evans, B.A. and Richards, R.I. Sequence and expression of mouse γ-renin. J. Biol. Chem. 263 (1988) 8565–8568. [PMID: 3288617]
[EC 3.4.21.54 created 1986]
 
 
EC 3.4.21.55     
Accepted name: venombin AB
Reaction: Selective cleavage at Arg┼ bonds in fibrinogen to form fibrin and release fibrinopeptides A and B
Other name(s): gabonase; okinaxobin II; Bitis gabonica venom serine proteinase; afaâcytin
Comments: From the venom of the Gaboon viper Bitis gabonica. Activates Factor XIII. Not inhibited by antithrombin III/heparin or hirudin, unlike EC 3.4.21.5, thrombin
References:
1.  Pirkle, H., Theodor, I., Miyada, D. and Simmons, G. Thrombin-like enzyme from the venom of Bitis gabonica. Purification, properties and coagulant actions. J. Biol. Chem. 261 (1986) 8830–8835. [PMID: 3522580]
[EC 3.4.21.55 created 1989]
 
 
EC 3.4.21.56      
Deleted entry: euphorbain. Now considered EC 3.4.21.25, cucumisin
[EC 3.4.21.56 created 1972 as EC 3.4.99.7, transferred 1989 to EC 3.4.21.56, deleted 1992]
 
 
EC 3.4.21.57     
Accepted name: leucyl endopeptidase
Reaction: Hydrolysis of proteins. Preferential cleavage: Leu┼ in small molecule substrates
Other name(s): plant Leu-proteinase; leucine-specific serine proteinase; leucine endopeptidase; spinach serine proteinase (leucine specific); spinach leucine-specific serine proteinase; Leu-proteinase
Comments: From leaves of the spinach plant (Spinacia oleracea)
References:
1.  Aducci, P., Ascenzi, P., Pierini, M. and Ballio, A. Purification and characterization of Leu-proteinase, the leucine specific serine proteinase from spinach (Spinacia oleracea L.) leaves. Plant Physiol. 81 (1986) 812–816. [PMID: 16664908]
2.  Aducci, P., Ascenzi, P. and Ballio, A. Esterolytic properties of leucine-proteinase, the leucine-specific serine proteinase from spinach (Spinacia oleracea L.). Plant Physiol. 82 (1986) 591–593. [PMID: 16665073]
[EC 3.4.21.57 created 1989]
 
 
EC 3.4.21.58      
Deleted entry:  prohormone serine proteinase
[EC 3.4.21.58 created 1989, deleted 1992]
 
 
EC 3.4.21.59     
Accepted name: tryptase
Reaction: Preferential cleavage: Arg┼, Lys┼, but with more restricted specificity than trypsin
Other name(s): mast cell tryptase; mast cell protease II; skin tryptase; lung tryptase; pituitary tryptase; mast cell neutral proteinase; mast cell tryptase; mast cell neutral proteinase; mast cell serine proteinase II; mast cell proteinase II; mast cell serine proteinase tryptase; rat mast cell protease II; tryptase M
Comments: Occurs as a tetrameric molecule with high affinity for heparin, in mast cell granules. In peptidase family S1 (trypsin family). Not inhibited by α1-proteinase inhibitor or α2-macroglobulin
References:
1.  Tanaka, T., McRae, B.J., Cho, K., Cook, R., Fraki, J.E., Johnson, D.A. and Powers, J.C. Mammalian tissue trypsin-like enzymes. Comparative reactivities of human skin tryptase, human lung tryptase, and bovine trypsin with peptide 4-nitroanilide and thioester substrates. J. Biol. Chem. 258 (1983) 13552–13557. [PMID: 6358206]
2.  Kido, H., Fukusen, N. and Katunuma, N. Chymotrypsin- and trypsin-type serine proteases in rat mast cells: properties and functions. Arch. Biochem. Biophys 239 (1985) 436–443. [PMID: 3890754]
3.  Cromlish, J.A., Seidah, N.G., Marcinkiewitz, M., Hamelin, J., Johnson, D.A. and Chrétien, M. Human pituitary tryptase: molecular forms, NH2-terminal sequence, immunocytochemical localization, and specificity with prohormone and fluorogenic substrates. J. Biol. Chem. 262 (1987) 1363–1373. [PMID: 3543004]
4.  Harvima, I.T., Schechter, N.M., Harvima, R.J. and Fräki, J.E. Human skin tryptase: purification, partial characterization and comparison with human lung tryptase. Biochim. Biophys. Acta 957 (1988) 71–80. [PMID: 3140898]
5.  Vanderslice, P., Ballinger, S.M., Tam, E.K., Goldstein, S.M., Craik, C.S. and Caughey, G. Human mast cell tryptase: multiple cDNAs and genes reveal a multigene serine protease family. Proc. Natl. Acad. Sci. USA 87 (1990) 3811–3815. [PMID: 2187193]
[EC 3.4.21.59 created 1992]
 
 
EC 3.4.21.60     
Accepted name: scutelarin
Reaction: Selective cleavage of Arg┼Thr and Arg┼Ile in prothrombin to form thrombin and two inactive fragments
Other name(s): taipan activator; Oxyuranus scutellatus prothrombin-activating proteinase
Comments: From the venom of the Taipan snake (Oxyuranus scutellatus). Converts prothrombin to thrombin. Specificity is similar to that of Factor Xa (EC 3.4.21.6). However, unlike Factor Xa this enzyme can cleave its target in the absence of coagulation Factor Va. Activity is potentiated by phospholipid and Ca2+ which binds via γ-carboxyglutamic acid residues. Similar enzymes are known from the venom of other Australian elapid snakes, including Pseudonaja textilis textilis, Oxyuranus microlepidotus and Demansia nuchalis affinis.
References:
1.  Walker, F.J., Owen, W.G. and Esmon, C.T. Characterization of the prothrombin activator from the venom of Oxyuranus scutellatus scutellatus (taipan venom). Biochemistry 19 (1980) 1020–1023. [PMID: 6986908]
2.  Speijer, H., Govers-Reimslag, J.W., Zwaal, R.F. and Rosing, J. Prothrombin activation by an activator from the venom of Oxyuranus scutellatus (taipan snake). J. Biol. Chem. 261 (1986) 13258–13267. [PMID: 3531198]
[EC 3.4.21.60 created 1978 as EC 3.4.99.28, transferred 1992 to EC 3.4.21.60, modified 2010, modified 2011]
 
 
EC 3.4.21.61     
Accepted name: kexin
Reaction: Cleavage of -Lys-Arg┼ and -Arg-Arg┼ bonds to process yeast α-factor pheromone and killer toxin precursors
Other name(s): yeast KEX2 protease; proteinase yscF; prohormone-processing endoprotease; paired-basic endopeptidase; yeast cysteine proteinase F (misleading); paired-basic endopeptidase; andrenorphin-Gly-generating enzyme; endoproteinase Kex2p; gene KEX2 dibasic proteinase; Kex 2p proteinase; Kex2 endopeptidase; Kex2 endoprotease; Kex2 endoproteinase; Kex2 protease; proteinase Kex2p; Kex2-like precursor protein processing endoprotease; prohormone-processing KEX2 proteinase; prohormone-processing proteinase; proprotein convertase; protease KEX2; Kex2 proteinase; Kex2-like endoproteinase
Comments: A Ca2+-activated peptidase of peptidase family S8, containing Cys near the active site His, and inhibited by p-mercuribenzoate. Similar enzymes occur in mammals.
References:
1.  Julius, D., Brake, A., Blair, L., Kunisawa, R. and Thorner, J. Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-α-factor. Cell 37 (1984) 1075–1089. [PMID: 6430565]
2.  Achstetter, T. and Wolf, D.H. Hormone processing and membrane-bound proteinases in yeast. EMBO J. 4 (1985) 173–177. [PMID: 3894003]
3.  Mizuno, K., Nakamura, T., Ohshima, T., Tanaka, S. and Matsuo, H. Yeast KEX2 gene encodes an endopeptidase homologous to subtilisin-like serine proteases. Biochem. Biophys. Res. Commun. 156 (1988) 246–254. [PMID: 2845974]
4.  Fuller, R.S., Brake, A. and Thorner, J. Yeast prohormone processing enzyme (KEX2 gene product) is a Ca2+-dependent serine protease. Proc. Natl. Acad. Sci. USA 86 (1989) 1434–1438. [PMID: 2646633]
5.  Mizuno, K., Nakamura, T., Ohshima, T., Tanaka, S. and Matsuo, H. Characterization of KEX2-encoded endopeptidase from yeast Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 159 (1989) 305–311. [PMID: 2647083]
[EC 3.4.21.61 created 1989 as EC 3.4.22.23, transferred 1992 to EC 3.4.21.61]
 
 
EC 3.4.21.62     
Accepted name: subtilisin
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds, and a preference for a large uncharged residue in P1. Hydrolyses peptide amides
Other name(s): alcalase; alcalase 0.6L; alcalase 2.5L; ALK-enzyme; bacillopeptidase A; bacillopeptidase B; Bacillus subtilis alkaline proteinase bioprase; bioprase AL 15; bioprase APL 30; colistinase; (see also comments); subtilisin J; subtilisin S41; subtilisin Sendai; subtilisin GX; subtilisin E; subtilisin BL; genenase I; esperase; maxatase; alcalase; thermoase PC 10; protease XXVII; thermoase; superase; subtilisin DY; subtilopeptidase; SP 266; savinase 8.0L; savinase 4.0T; kazusase; protease VIII; opticlean; Bacillus subtilis alkaline proteinase; protin A 3L; savinase; savinase 16.0L; savinase 32.0 L EX; orientase 10B; protease S
Comments: Subtilisin is a serine endopeptidase, type example of peptidase family S8. It contains no cysteine residues (although these are found in homologous enzymes). Species variants include subtilisin BPN′ (also subtilisin B, subtilopeptidase B, subtilopeptidase C, Nagarse, Nagarse proteinase, subtilisin Novo, bacterial proteinase Novo) and subtilisin Carlsberg (subtilisin A, subtilopeptidase A, alcalase Novo). Similar enzymes are produced by various Bacillus subtilis strains and other Bacillus species [1,3]
References:
1.  Ottesen, M. and Svendsen, I. The subtilisins. Methods Enzymol. 19 (1970) 199–215.
2.  Markland, F.S. and Smith, E.L. Subtilisins: primary structure, chemical and physical properties. In: Boyer, P.D. (Ed.), The Enzymes, 3rd edn, vol. 3, Academic Press, New York, 1971, pp. 561–608.
3.  Philipp, M. and Bender, M.L. Kinetics of subtilisin and thiolsubtilisin. Mol. Cell. Biochem. 51 (1983) 5–32. [PMID: 6221910]
4.  Nedkov, P., Oberthür, W. and Braunitzer, G. Determination of the complete amino acid sequence of subtilisin DY and its comparison with the primary structures of the subtilisins BPN, Carlsberg and amylosacchariticus. Biol. Chem. Hoppe-Seyler 366 (1985) 421–430. [PMID: 3927935]
5.  Ikemura, H., Takagi, H. and Inouye, M. Requirement of pro-sequence for the production of active subtilisin E in Escherichia coli. J. Biol. Chem. 262 (1987) 7859–7864. [PMID: 3108260]
6.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
[EC 3.4.21.62 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.63     
Accepted name: oryzin
Reaction: Hydrolysis of proteins with broad specificity, and of Bz-Arg-OEt > Ac-Tyr-OEt. Does not hydrolyse peptide amides
Other name(s): Aspergillus alkaline proteinase; aspergillopeptidase B; API 21; aspergillopepsin B; aspergillopepsin F; Aspergillus candidus alkaline proteinase; Aspergillus flavus alkaline proteinase; Aspergillus melleus semi-alkaline proteinase; Aspergillus oryzae alkaline proteinase; Aspergillus parasiticus alkaline proteinase; Aspergillus serine proteinase; Aspergillus sydowi alkaline proteinase; Aspergillus soya alkaline proteinase; Aspergillus melleus alkaline proteinase; Aspergillus sulphureus alkaline proteinase; prozyme; P 5380; kyorinase; seaprose S; semi-alkaline protease; sumizyme MP; prozyme 10; onoprose; onoprose SA; protease P; promelase
Comments: A peptidase of family S8 (subtilisin family), not containing cysteine, that is the predominant extracellular alkaline endopeptidase of the mold Aspergillus oryzae. Identical or closely related enzymes are produced by A. flavus and A. sojae [2,3,4]
References:
1.  Nakagawa, Y. Alkaline proteinases from Aspergillus. Methods Enzymol. 19 (1970) 581–591.
2.  Hayashi, K. and Terada, M. Some characteristics of hydrolysis of synthetic substrates and proteins by the alkaline proteases from Aspergillus sojae. Agric. Biol. Chem. 36 (1972) 1755–1765.
3.  Turková, J., Mikes, O., Hayashi, K., Danno, G. and Polgár, L. Alkaline proteinases of the genus Aspergillus. Biochim. Biophys. Acta 257 (1972) 257–263. [PMID: 4623338]
4.  Morihara, K., Oka, T. and Tsuzuki, H. Comparative study of various serine alkaline proteinases from microorganisms. Esterase activity against N-acylated peptide ester substrates. Arch. Biochem. Biophys. 165 (1974) 72–79. [PMID: 4441086]
5.  Spadari, S., Subramanian, A.R. and Kalnitsky, G. Highly restricted specificity of the serine proteinase aspergillopeptidase B. Biochim. Biophys. Acta 359 (1974) 267–272. [PMID: 4859351]
[EC 3.4.21.63 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.64     
Accepted name: peptidase K
Reaction: Hydrolysis of keratin, and of other proteins with subtilisin-like specificity. Hydrolyses peptide amides
Other name(s): Tritirachium alkaline proteinase; Tritirachium album serine proteinase; proteinase K; Tritirachium album proteinase K; endopeptidase K
Comments: From the mold Tritirachium album Limber. A peptidase of family S8 (subtilisin family) containing two disulfide bridges and one free Cys near the active site His. Formerly included in EC 3.4.21.14
References:
1.  Ebeling, W., Hennrich, N., Klockow, M., Metz, H., Orth, H.D. and Lang, H. Proteinase K from Tritirachium album Limber. Eur. J. Biochem. 47 (1974) 91–97. [PMID: 4373242]
2.  Morihara, K. and Tsuzuki, H. Specificity of proteinase K from Tritirachium album Limber for synthetic peptides. Agric. Biol. Chem. 39 (1975) 1489–1492.
3.  Kraus, E., Klitz, H.H. and Fembert, U.F. The specificity of proteinase K against oxidized insulin B chain. Hoppe-Seyler's Z. Physiol. Chem. 357 (1976) 233–237. [PMID: 943367]
4.  Jany, K.-D., Lederer, G. and Mayer, B. Amino acid sequence of proteinase K from the mold Tritirachium album Limber. FEBS Lett. 199 (1986) 139–144.
5.  Betzel, C., Teplyakov, A.V., Harutyunyan, E.H., Saenger, W. and Wilson, K.S. Thermitase and proteinase K: a comparison of the refined three-dimensional structures of the native enzymes. Protein Engineering 3 (1990) 161–172. [PMID: 2184432]
[EC 3.4.21.64 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.65     
Accepted name: thermomycolin
Reaction: Rather nonspecific hydrolysis of proteins. Preferential cleavage: Ala┼, Tyr┼, Phe┼ in small molecule substrates
Other name(s): thermomycolase
Comments: A peptidase of family S8 (subtilisin family) from the thermophilic fungus Malbranchea pulchella var. sulfurea containing Cys, but not inhibited by p-mercuribenzoate. Very thermostable. Formerly included in EC 3.4.21.14
References:
1.  Gaucher, G.M. and Stevenson, K.J. Thermomycolin. Methods Enzymol. 45 (1976) 415–433. [PMID: 1012007]
[EC 3.4.21.65 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.66     
Accepted name: thermitase
Reaction: Hydrolysis of proteins, including collagen
Other name(s): thermophilic Streptomyces serine proteinase; Thermoactinomyces vulgaris serine proteinase
Comments: A peptidase of family S8 (subtilisin family) from Thermoactinomyces vulgaris containing a single Cys, near the active site His, and inhibited by p-mercuribenzoate. The N-terminal extension of the polypeptide chain relative to subtilisin contributes to Ca2+-binding and the high thermostability. The amino acid composition and properties of the thermostable enzyme from Streptomyces rectus var. proteolyticus (formerly included in EC 3.4.21.14) are closely similar [1,2].
References:
1.  Mizusawa, K. and Yoshida, F. Thermophilic Streptomyces alkaline proteinase. J. Biol. Chem. 247 (1972) 6978–6984. [PMID: 4711613]
2.  Borgia, P. and Campbell, L. Properties of two homologous alkaline proteases from Streptomyces rectus. J. Bacteriol. 123 (1974) 1109–1115. [PMID: 4373436]
3.  Kleine, R. Properties of thermitase, a thermostable serine protease from Thermoactinomyces vulgaris. Acta Biol. Med. Ger. 41 (1982) 89–102. [PMID: 7051706]
4.  Meloun, B., Baudyš, M., Kostka, V., Hausdorf, G., Frömmel, C. and Höhne, W.E. Complete primary structure of thermitase from Thermoactinomyces vulgaris and its structural features related to the subtilisin-type proteinases. FEBS Lett. 183 (1985) 195–200.
5.  Teplyakov, A.V., Kuranova, I.P., Harutyunyan, E.H., Vainshtein, B.K., Frömmel, C., Höhne, W.E. and Wilson, K.S. Crystal structure of thermitase at 1.4 Å resolution. J. Mol. Biol. 214 (1990) 261–279. [PMID: 2196375]
[EC 3.4.21.66 created 1992]
 
 
EC 3.4.21.67     
Accepted name: endopeptidase So
Reaction: Hydrolysis of proteins, but not Bz-Tyr-OEt, Ac-Phe-β-naphthylester, or Bz-Arg-OEt
Other name(s): E. coli cytoplasmic proteinase; proteinase So; Escherichia coli serine proteinase So
Comments: An Escherichia coli cytoplasmic endopeptidase formerly included in EC 3.4.21.14. Inhibited by Tos-Phe-CH2Cl, but not by Tos-Lys-CH2Cl
References:
1.  Goldberg, A.L., Swamy, K.H.S., Chung, C.H. and Larimore, F.S. Proteases in Escherichia coli. Methods Enzymol. 80 (1981) 680–702. [PMID: 7043205]
2.  Chung, C.H. and Goldberg, A.L. Purification and characterization of protease So, a cytoplasmic serine protease in Escherichia coli. J. Bacteriol. 154 (1983) 231–238. [PMID: 6339474]
[EC 3.4.21.67 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.68     
Accepted name: t-plasminogen activator
Reaction: Specific cleavage of Arg┼Val bond in plasminogen to form plasmin
Other name(s): tissue plasminogen activator; plasminogen activator, tissue-type; tissue-type plasminogen activator; tPA; t-PA
Comments: A peptidase of family S1 (trypsin family) from a wide variety of mammalian tissues, especially endothelial cells. Secreted as a single chain precursor which is cleaved to a two-chain form by plasmin. Activity is considerably enhanced by fibrin. Formerly included in EC 3.4.21.31 and EC 3.4.99.26
References:
1.  Pennica, D., Holmes, W.E., Kohr, W.J., Harkins, R.N., Vehar, G.A., Ward, C.A., Bennett, W.F., Yelverton, E., Seeburg, P.H., Heyneker, H.L., Goeddel, D.V. and Collen, D. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 301 (1983) 214–221. [PMID: 6337343]
2.  Loskutoff, D.J. and Schleef, R.R. Plasminogen activators and their inhibitors. Methods Enzymol. 163 (1988) 293–302. [PMID: 3148826]
3.  Petersen, L.C., Johannessen, M., Forster, D., Kumar, A. and Mulvihill, E. The effect of polymerised fibrin on the catalytic activities of one-chain tissue-type plasminogen activator as revealed by an analogue resistant to plasmin cleavage. Biochim. Biophys. Acta 952 (1988) 245–254. [PMID: 2962643]
4.  Verheijen, J.H. Tissue-type plasminogen activator and fast-acting plasminogen activator inhibitor in plasma. Methods Enzymol. 163 (1988) 302–309. [PMID: 3148827]
5.  Gerard, R.D. and Meidell, R.S. Regulation of tissue plasminogen activator expression. Annu. Rev. Physiol. 51 (1989) 245–262. [PMID: 2496643]
6.  Collen, D., Lijnen, H. R. and Verstraete, M. The fibrinolytic system and its disorders. In: Handin, R.I., Lux, S.E. and Stossel, J.P. (Eds), Blood: Principles and Practice of Hematology, 2nd edn, J.B.Lippincott Company, Philadelphia, 1990.
[EC 3.4.21.68 created 1972 as EC 3.4.99.26, transferred 1978 as EC 3.4.21.31, part transferred 1992 to EC 3.4.21.68]
 
 
EC 3.4.21.69     
Accepted name: protein C (activated)
Reaction: Degradation of blood coagulation factors Va and VIIIa
Other name(s): blood-coagulation factor XIVa; activated blood coagulation factor XIV; activated protein C; autoprothrombin II-A; protein Ca; APC; GSAPC
Comments: A peptidase of family S1 (trypsin family), one of the γ-carboxyglutamic acid-containing coagulation factors. Formed from protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin, or by serine endopeptidases present in several snake venoms
References:
1.  Esmon, C.T. The regulation of natural anticoagulant pathways. Science 235 (1987) 1348–1352. [PMID: 3029867]
2.  Esmon, C.T. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J. Biol. Chem. 264 (1989) 4743–4746. [PMID: 2538457]
[EC 3.4.21.69 created 1992]
 
 
EC 3.4.21.70     
Accepted name: pancreatic endopeptidase E
Reaction: Preferential cleavage: Ala┼. Does not hydrolyse elastin
Other name(s): cholesterol-binding proteinase; proteinase E; cholesterol-binding serine proteinase; pancreatic protease E; pancreatic proteinase E; cholesterol-binding pancreatic proteinase; CBPP; pancreas E proteinase
Comments: A peptidase of family S1 (trypsin family) from pancreatic juice. Unlike elastases, has an acidic pI. Binds cholesterol
References:
1.  Mallory, P.A. and Travis, J. Human pancreatic enzymes: purification and characterization of a nonelastolytic enzyme, protease E, resembling elastase. Biochemistry 14 (1975) 722–729. [PMID: 234742]
2.  Shen, W., Fletcher, T.S. and Largman, C. Primary structure of human pancreatic protease E determined by sequence analysis of the cloned mRNA. Biochemistry 26 (1987) 3447–3452. [PMID: 3477287]
[EC 3.4.21.70 created 1992]
 
 
EC 3.4.21.71     
Accepted name: pancreatic elastase II
Reaction: Preferential cleavage: Leu┼, Met┼ and Phe┼. Hydrolyses elastin
Other name(s): pancreatic elastase 2
Comments: A peptidase of family S1 (trypsin family) formed by activation of proelastase II from mammalian pancreas by trypsin. Usually, only one of the pancreatic elastases (see also EC 3.4.21.36) is expressed in a given species; human pancreatic elastase is of type II
References:
1.  Fletcher, T.S., Shen, W.-F. and Largman, C. Primary structure of human pancreatic elastase 2 determined by sequence analysis of the cloned mRNA. Biochemistry 26 (1987) 7256–7261. [PMID: 3427074]
2.  Shirasu, Y., Yoshida, H., Matsuki, S., Takemura, K., Ikeda, N., Shimada, Y., Ozawa, T., Mikayama, T., Iijima, H., Ishida, A., Sato, Y., Tamai, Y., Tanaka, J. and Ikenaga, H. Molecular cloning and expression in Escherichia coli of a cDNA encoding human pancreatic elastase 2. J. Biochem. (Tokyo) 102 (1987) 1555–1563. [PMID: 2834346]
[EC 3.4.21.71 created 1992]
 
 
EC 3.4.21.72     
Accepted name: IgA-specific serine endopeptidase
Reaction: Cleavage of immunoglobulin A molecules at certain Pro┼ bonds in the hinge region. No small molecule substrates are known
Other name(s): IgA protease; IgA proteinase; IgA-specific proteinase; immunoglobulin A protease; immunoglobulin A proteinase
Comments: Species variants differing slightly in specificity are secreted by Gram-negative bacteria Neisseria gonorrhoeae and Haemophilus influenzae. Type example of peptidase family S6. Some other bacterial endopeptidases with similar specificity are of metallo- type (see EC 3.4.24.13, IgA-specific metalloendopeptidase)
References:
1.  Plaut, A.G. The IgA1 proteases of pathogenic bacteria. Annu. Rev. Microbiol. 37 (1983) 603–622. [PMID: 6416146]
2.  Bachovchin, W.W., Plaut, A.G., Flentke, G.R., Lynch, M. and Kettner, C.A. Inhibition of IgA1 proteinases from Neisseria gonorrhoeae and Hemophilus influenzae by peptide prolyl boronic acids. J. Biol. Chem. 265 (1990) 3738–3743. [PMID: 2105953]
[EC 3.4.21.72 created 1992]
 
 
EC 3.4.21.73     
Accepted name: u-plasminogen activator
Reaction: Specific cleavage of Arg┼Val bond in plasminogen to form plasmin
Other name(s): urokinase; urinary plasminogen activator; cellular plasminogen activator; urokinase-type plasminogen activator; double-chain urokinase-type plasminogen activator; two-chain urokinase-type plasminogen activator; urokinase plasminogen activator; uPA; u-PA; abbokinase; urinary esterase A
Comments: Formed from the inactive precursor by action of plasmin or plasma kallikrein. Differs in structure from t-plasminogen activator (EC 3.4.21.68), and does not bind to fibrin. In peptidase family S1 (trypsin family). Formerly included in EC 3.4.21.31 and EC 3.4.99.26
References:
1.  Lottenberg, R., Christiansen, U., Jackson, C.M. and Coleman, P.L. Assay of coagulation proteases using peptide chromogenic and fluorogenic substrates. Methods Enzymol. 80 (1981) 341–361. [PMID: 6210826]
2.  Loskutoff, D.J. and Schleef, R.R. Plasminogen activators and their inhibitors. Methods Enzymol. 163 (1988) 293–302. [PMID: 3148826]
3.  Saksela, O. and Rifkin, D.B. Cell-associated plasminogen activation: regulation and physiological functions. Annu. Rev. Cell Biol. 4 (1988) 93–126. [PMID: 3143380]
4.  Collen, D., Lijnen, H. R. and Verstraete, M. The fibrinolytic system and its disorders. In: Handin, R.I., Lux, S.E. and Stossel, J.P. (Eds), Blood: Principles and Practice of Hematology, 2nd edn, J.B.Lippincott Company, Philadelphia, 1990.
5.  Lijnen, H.R., Van Hoef, B., Nelles, L. and Collen, D. Plasminogen activation with single-chain urokinase-type plasminogen activator (scu-PA). Studies with active site mutagenized plasminogen (Ser740→Glu). J. Biol. Chem. 265 (1990) 5232–5236. [PMID: 1969415]
[EC 3.4.21.73 created 1972 as EC 3.4.99.26, transferred 1978 as EC 3.4.21.31, part transferred 1992 to EC 3.4.21.73]
 
 
EC 3.4.21.74     
Accepted name: venombin A
Reaction: Selective cleavage of Arg┼ bond in fibrinogen, to form fibrin, and release fibrinopeptide A. The specificity of further degradation of fibrinogen varies with species origin of the enzyme
Other name(s): α-fibrinogenase; habutobin; zinc metalloproteinase Cbfib1.1; zinc metalloproteinase Cbfib1.2; zinc metalloproteinase Cbfib2; ancrod; (see also Comments)
Comments: A somewhat thrombin-like enzyme from venoms of snakes of the viper/rattlesnake group. Species variants of the enzyme include ancrod from Agkistrodon rhodostoma (Malayan pit viper) (formerly EC 3.4.21.28) [1], batroxobin from Bothrops atrox (South American pit viper) (formerly EC 3.4.21.29) [2,5] and crotalase from Crotalus adamanteus (Eastern diamondback rattlesnake) (formerly EC 3.4.21.30) [3,4]. In peptidase family S1 (trypsin family). Does not require activation by Ca2+
References:
1.  Nolan, C., Hall, L.S. and Barlow, G.H. Ancrod, the coagulating enzyme from Malayan pit viper (Agkistrodon rhodostoma) venom. Methods Enzymol. 45 (1976) 205–213. [PMID: 1011992]
2.  Stocker, K. and Barlow, G.H. The coagulant enzyme from Bothrops atrox venom (batroxobin). Methods Enzymol. 45 (1976) 214–223. [PMID: 1011993]
3.  Markland, F.S., Kettner, C., Schiffmann, S., Shaw, E., Bajwa, S.S., Reddy, K.N.N., Kirakossian, H., Patkos, G.B., Theodor, I. and Pirkle, H. Kallikrein-like activity of crotalase, a snake venom enzyme that clots fibrinogen. Proc. Natl. Acad. Sci. USA 79 (1982) 1688–1692. [PMID: 7043462]
4.  Simmons, G., Bundalian, M., Theodor, I., Martinoli, J. and Pirkle, H. Action of crotalase, an enzyme with thrombin-like and kallikrein-like specificities, on tripeptide nitroanilide derivatives. Thromb. Res. 40 (1985) 555–561. [PMID: 2934864]
5.  Itoh, N., Tanaka, N., Funakoshi, I., Kawasaki, T., Mihashi, S. and Yamashina, I. Organisation of the gene for batroxobin, a thrombin-like snake venom enzyme. Homology with the trypsin/kallikrein gene family. J. Biol. Chem. 263 (1988) 7628–7631. [PMID: 3163691]
[EC 3.4.21.74 created 1992 (EC 3.4.21.28, EC 3.4.21.29 and 3.4.21.30 all created 1978 and incorporated 1992)]
 
 
EC 3.4.21.75     
Accepted name: furin
Reaction: Release of mature proteins from their proproteins by cleavage of -Arg-Xaa-Yaa-Arg┼ bonds, where Xaa can by any amino acid and Yaa is Arg or Lys. Releases albumin, complement component C3 and von Willebrand factor from their respective precursors
Other name(s): prohormone convertase; dibasic processing enzyme; PACE; paired basic amino acid cleaving enzyme; paired basic amino acid converting enzyme; serine proteinase PACE; PC1; SPC3; proprotein convertase
Comments: One of a group of peptidases in peptidase family S8 (subtilisin family) that is structurally and functionally similar to kexin. All are activated by Ca2+, contain Cys near the active site His, and are inhibited by p-mercuribenzoate. At least three related enzymes are recognized in mammals: PC2, PC3 and PC4, which have somewhat different specificities
References:
1.  Van de Ven, W.J.M., Voorberg, J., Fontijn, R., Pannekoek, H., van den Ouweland, A.M.W., van Duijnhoven, H.L.P., Roebroek, A.J.M. and Siezen, R.J. Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol. Biol. Rep. 14 (1990) 265–275. [PMID: 2094803]
2.  Van de Ven, W.J.M., Creemers, J.W.M. and Roebroek, A.J.M. Furin: the prototype mammalian subtilisin-like proprotein-processing enzyme. Endoproteolytic cleavage at paired basic residues of proproteins of the eukaryotic secretory pathway. Enzyme 45 (1991) 257–270. [PMID: 1843280]
3.  Hatsuzawa, K., Murakami, K. and Nakayama, K. Molecular and enzymatic properties of furin, a Kex2-like endoprotease involved in precursor cleavage at Arg-X-Lys/Arg-Arg sites. J. Biochem. (Tokyo) 111 (1992) 296–301. [PMID: 1587790]
4.  Seidah, N.G. and Chrétien, M. Proprotein and prohormone convertases of the subtilisin family: recent developments and future perspectives. Trends Endocrinol. Metab. 3 (1992) 133–140. [PMID: 18407092]
5.  Steiner, D.F., Smeekens, S.P., Ohagi, S. and Chan, S.J. The new enzymology of precursor processing endoproteases. J. Biol. Chem. 267 (1992) 23435–23438. [PMID: 1429684]
[EC 3.4.21.75 created 1993]
 
 
EC 3.4.21.76     
Accepted name: myeloblastin
Reaction: Hydrolysis of proteins, including elastin, by preferential cleavage: -Ala┼ > -Val┼
Other name(s): leukocyte proteinase 3; leukocyte proteinase 4; Wegener’s granulomatosis autoantigen; proteinase PR-3; proteinase-3; PMNL proteinase
Comments: From polymorphonuclear leukocyte granules. In peptidase family S1 (trypsin family). Not inhibited by secretory leukocyte proteinase inhibitor
References:
1.  Labbaye, C., Musette, P. and Cayre, Y.E. Wegener autoantigen and myeloblastin are encoded by a single mRNA. Proc. Natl. Acad. Sci. USA 88 (1991) 9253–9256. [PMID: 1681549]
2.  Rao, N.V., Wehner, N.G., Marshall, B.C., Gray, W.R., Gray, B.H. and Hoidal, J.R. Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase. Structural and functional properties. J. Biol. Chem. 266 (1991) 9540–9548. [PMID: 2033050]
3.  Brubaker, M.J., Groutas, W.C., Hoidal, J.R. and Rao, N.V. Human neutrophil proteinase 3: mapping of the substrate binding site using peptidyl thiobenzyl esters. Biochem. Biophys. Res. Commun. 188 (1992) 1318–1324. [PMID: 1445363]
4.  Kam, C.-M., Kerrigan, J.E., Dolman, K.M., Goldschmeding, R., von dem Borne, A.E.G.K. and Powers, J.C. Substrate and inhibitor studies on proteinase 3. FEBS Lett. 297 (1992) 119–123. [PMID: 1551417]
[EC 3.4.21.76 created 1993]
 
 
EC 3.4.21.77     
Accepted name: semenogelase
Reaction: Preferential cleavage: -Tyr┼
Other name(s): prostate-specific antigen; α-seminoprotein; seminin; P-30 antigen; antigen (human clone HPSA-1 prostate-specific protein moiety reduced); γ-seminoglycoprotein (human protein moiety reduced); γ-SM; antigen PSA (human prostate-specific); human glandular kallikrein; antigen PSA (human clone 5P1 protein moiety reduced)
Comments: A peptidase of family S1 (trypsin family) from seminal plasma. Slowly inhibited by α1-antichymotrypsin
References:
1.  Digby, M., Zhang, X.-Y. and Richards, R.I. Human prostate specific antigen (PSA) gene: structure and linkage to the kallikrein-like gene, hGK-1. Nucleic Acids Res. 15 (1989) 2137. [PMID: 2467258]
2.  Christensson, A., Laurell, C.-B. and Lilja, H. Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur. J. Biochem. 194 (1990) 755–763. [PMID: 1702714]
[EC 3.4.21.77 created 1993]
 
 
EC 3.4.21.78     
Accepted name: granzyme A
Reaction: Hydrolysis of proteins, including fibronectin, type IV collagen and nucleolin. Preferential cleavage: -Arg┼, -Lys┼ >> -Phe┼ in small molecule substrates
Other name(s): CTLA3; HuTPS; T-cell associated protease 1; cytotoxic T lymphocyte serine protease; TSP-1; T-cell derived serine proteinase
Comments: From cytotoxic T lymphocyte granules. In peptidase family S1 (trypsin family). The human enzyme does not cleave Phe┼-
References:
1.  Simon, M.M., Hoschützky, H., Fruth, U., Simon, H.-G. and Kramer, M.D. Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes. EMBO J. 5 (1986) 3267–3274. [PMID: 3545816]
2.  Gershenfeld, H.K., Hershberger, R.J., Shows, T.B. and Weissman, I.L. Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease. Proc. Natl. Acad. Sci. USA 85 (1988) 1184–1188. [PMID: 3257574]
3.  Odake, S., Kam, C.-M., Narasimhan, L., Poe, M., Blake, J.T., Krahenbuhl, O., Tschopp, J. and Powers, J.C. Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins. Biochemistry 30 (1991) 2217–2227. [PMID: 1998680]
[EC 3.4.21.78 created 1993]
 
 
EC 3.4.21.79     
Accepted name: granzyme B
Reaction: Preferential cleavage: -Asp┼ >> -Asn┼ > -Met┼, -Ser┼
Other name(s): CTLA1; CCPII; cytotoxic cell proteinase-1; granzyme G; granzyme H; CCP1 proteinase
Comments: From cytotoxic T lymphocyte granules. In peptidase family S1 (trypsin family)
References:
1.  Schmid, J. and Weissmann, C. Induction of mRNA for a serine protease and a β-thromboglobulin-like protein in mitogen-stimulated human leukocytes. J. Immunol. 139 (1987) 250–256. [PMID: 2953813]
2.  Odake, S., Kam, C.-M., Narasimhan, L., Poe, M., Blake, J.T., Krahenbuhl, O., Tschopp, J. and Powers, J.C. Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins. Biochemistry 30 (1991) 2217–2227. [PMID: 1998680]
3.  Poe, M., Blake, J.T., Boulton, D.A., Gammon, M., Sigal, N.H., Wu, J.K. and Zweerink, H.J. Human cytotoxic lymphocyte granzyme B. Its purification from granules and the characterization of substrate and inhibitor specificity. J. Biol. Chem. 266 (1991) 98–103. [PMID: 1985927]
[EC 3.4.21.79 created 1993]
 
 
EC 3.4.21.80     
Accepted name: streptogrisin A
Reaction: Hydrolysis of proteins with specificity similar to chymotrypsin
Other name(s): Streptomyces griseus protease A; protease A; proteinase A; Streptomyces griseus proteinase A; Streptomyces griseus serine proteinase 3; Streptomyces griseus serine proteinase A
Comments: From Streptomyces griseus. A component of Pronase, in family S1 (trypsin family). Not inhibited by Tos-Phe-CH2Cl or ovomucoid
References:
1.  Johnson, P. and Smillie, L.B. The disulfide bridge sequences of a serine protease of wide specificity from Streptomyces griseus. Can. J. Biochem. 49 (1971) 548–562. [PMID: 5575653]
2.  Sielecki, A.R., Hendrickson, W.A., Broughton, C.G., Delbaere, L.T.J., Brayer, G.D. and James, M.N.G. Protein structure refinement: Streptomyces griseus serine protease A at 1.8 Å resolution. J. Mol. Biol. 134 (1979) 781–804. [PMID: 119870]
3.  James, M.N.G., Sielecki, A.R., Brayer, G.D., Delbaere, L.T.J. and Bauer, C.-A. Structures of product and inhibitor complexes of Streptomyces griseus protease A at 1.8 Å resolution. J. Mol. Biol. 144 (1980) 43–88. [PMID: 6783761]
4.  Delbaere, L.T.J. and Brayer, G.D. The 1.8 Å structure of the complex between chymostatin and Streptomyces griseus protease A. A model for serine protease catalytic tetrahedral intermediates. J. Mol. Biol. 183 (1985) 89–103. [PMID: 3892018]
5.  Henderson, G., Krygsman, P., Liu, C.J., Davey, C.C. and Malek, L.T. Characterization and structure of genes for proteases A and B from Streptomyces griseus. J. Bacteriol. 169 (1987) 3778–3784. [PMID: 3112129]
[EC 3.4.21.80 created 1993]
 
 
EC 3.4.21.81     
Accepted name: streptogrisin B
Reaction: Hydrolysis of proteins with trypsin-like specificity
Other name(s): Streptomyces griseus protease B; pronase B; serine proteinase B; Streptomyces griseus proteinase B; Streptomyces griseus proteinase 1; Streptomyces griseus serine proteinase B
Comments: From Streptomyces griseus. A component of Pronase, in peptidase family S1 (trypsin family), distinct from Streptomyces trypsin
References:
1.  Jurasek, L., Fackre, D. and Smillie, L.B. Remarkable homology about the disulfide bridges of a trypsin-like enzyme from Streptomyces griseus. Biochem. Biophys. Res. Commun. 37 (1969) 99–105. [PMID: 4899581]
2.  Fujinaga, M., Read, R.J., Sielecki, A., Ardelt, W., Laskowski, M., Jr. and James, M.N.G. Refined crystal structure of the molecular complex of Streptomyces griseus protease B, a serine protease, with the third domain of the ovomucoid inhibitor from turkey. Proc. Natl Acad. Sci. USA 79 (1982) 4868–4872. [PMID: 6750612]
3.  Read, R.J., Fujinaga, M., Sielecki, A.R. and James, M.N.G. Structure of the complex of Streptomyces griseus protease B and the third domain of turkey ovomucoid inhibitor at 1.8-Å resolution. Biochemistry 22 (1983) 4420–4433. [PMID: 6414511]
4.  Henderson, G., Krygsman, P., Liu, C.J., Davey, C.C. and Malek, L.T. Characterization and structure of genes for proteases A and B from Streptomyces griseus. J. Bacteriol. 169 (1987) 3778–3784. [PMID: 3112129]
5.  Greenblatt, H.M., Ryan, C.A. and James, M.N.G. Structure of the complex of Streptomyces griseus proteinase B and polypeptide chymotrypsin inhibitor-1 from Russet Burbank potato tubers at 2.1 Å resolution. J. Mol. Biol. 205 (1989) 201–228. [PMID: 2494344]
[EC 3.4.21.81 created 1993]
 
 
EC 3.4.21.82     
Accepted name: glutamyl endopeptidase II
Reaction: Preferential cleavage: -Glu┼ >> -Asp┼ . Preference for Pro or Leu at P2 and Phe at P3. Cleavage of -Glu┼Asp- and -Glu┼Pro- bonds is slow
Other name(s): GluSGP
Comments: From Streptomyces griseus. A peptidase of family S1 (trypsin family). Inhibited by [Leu18→Glu]-modified turkey ovomucoid third domain
References:
1.  Yoshida, N., Tsuruyama, S., Nagata, K., Hirayama, K., Noda, K. and Makisumi, S. Purification and characterization of an acidic amino acid specific endopeptidase of Streptomyces griseus obtained from a commercial preparation (Pronase). J. Biochem. (Tokyo) 104 (1988) 451–456. [PMID: 3149277]
2.  Komiyama, T., Bigler, T.L., Yoshida, N., Noda, K. and Laskowski, M., Jr. Replacement of P1 Leu18 by Glu18 in the reactive site of turkey ovomucoid third domain converts it into a strong inhibitor of Glu-specific Streptomyces griseus Proteinase (GluSGP). J. Biol. Chem. 266 (1991) 10727–10730. [PMID: 1674942]
3.  Nagata, K., Yoshida, N., Ogata, F., Araki, M. and Noda, K. Subsite mapping of an acidic amino acid-specific endopeptidase from Streptomyces griseus, GluSGP, and protease V8. J. Biochem. (Tokyo) 110 (1991) 859–862. [PMID: 1794975]
4.  Svendsen, I., Jensen, M.R. and Breddam, K. The primary structure of the glutamic acid-specific protease of Streptomyces griseus. FEBS Lett. 292 (1991) 165–167. [PMID: 1959600]
5.  Breddam, K. and Meldal, M. Substrate preferences of glutamic-acid-specific endopeptidases assessed by synthetic peptide substrates based on intramolecular fluorescence quenching. Eur. J. Biochem. 206 (1992) 103–107. [PMID: 1587264]
[EC 3.4.21.82 created 1993]
 
 
EC 3.4.21.83     
Accepted name: oligopeptidase B
Reaction: Hydrolysis of -Arg┼, -Lys┼ bonds in oligopeptides, even when P1′ residue is proline
Other name(s): protease II; Escherichia coli alkaline proteinase II; protease II
Comments: Known from Escherichia coli. Inhibited by Tos-Lys-CH2Cl. In peptidase family S9 (prolyl oligopeptidase family)
References:
1.  Kanatani, A., Masuda, T., Shimoda, T., Misoka, F., Lin, X.S., Yoshimoto, T. and Tsuru, D. Protease II from Escherichia coli: sequencing and expression of the enzyme gene and characterization of the expressed enzyme. J. Biochem. (Tokyo) 110 (1991) 315–320. [PMID: 1769955]
[EC 3.4.21.83 created 1993]
 
 
EC 3.4.21.84     
Accepted name: limulus clotting factor C
Reaction: Selective cleavage of -Arg103┼Ser- and -Ile124┼Ile- bonds in limulus clotting factor B to form factor B. Cleavage of -Pro-Arg┼ bonds in synthetic substrates
Other name(s): factor C; limulus factor C
Comments: From the hemocyte granules of the horseshoe crabs Limulus and Tachypleus. Factor C is activated by Gram-negative bacterial lipopolysaccharides and chymotrypsin. Inhibited by antithrombin III. In peptidase family S1 (trypsin family)
References:
1.  Nakamura, T., Morita, T. and Iwanaga, S. Lipopolysaccharide-sensitive serine-protease zymogen (factor C) found in Limulus hemocytes. Isolation and characterization. Eur. J. Biochem. 154 (1986) 511–521. [PMID: 3512266]
2.  Muta, T., Miyata, T., Misumi, Y., Tokunaga, F., Nakamura, T., Toh, Y., Ikehara, Y. and Iwanaga, S. Limulus factor C. An endotoxin-sensitive serine protease zymogen with a mosaic structure of complement-like, epidermal growth factor-like, and lectin-like domains. J. Biol. Chem. 266 (1991) 6554–6561. [PMID: 2007602]
3.  Tokunaga, F., Nakajima, H. and Iwanaga, S. Further studies on lipopolysaccharide-sensitive serine protease zymogen (factor C): its isolation from Limulus polyphemus hemocytes and identification as an intracellular zymogen activated by α-chymotrypsin, not by trypsin. J. Biochem. (Tokyo) 109 (1991) 150–157. [PMID: 2016264]
[EC 3.4.21.84 created 1993]
 
 
EC 3.4.21.85     
Accepted name: limulus clotting factor B
Reaction: Selective cleavage of -Arg98┼Ile- bond in limulus proclotting enzyme to form active clotting enzyme
Comments: From the hemocyte granules of the horseshoe crabs Limulus and Tachypleus. Factor B is activated by limulus clotting factor C. In peptidase family S1 (trypsin family)
References:
1.  Nakamura, T., Horiuchi, T., Morita, T. and Iwanaga, S. Purification and properties of intracellular clotting factor, factor B, from horseshoe crab (Tachypleus tridentatus) hemocytes. J. Biochem. (Tokyo) 99 (1986) 847–857. [PMID: 3519594]
[EC 3.4.21.85 created 1993]
 
 
EC 3.4.21.86     
Accepted name: limulus clotting enzyme
Reaction: Selective cleavage of -Arg18┼ and -Arg47┼ bonds in coagulogen to form coagulin and fragments
Other name(s): clotting enzyme
Comments: From the hemocyte granules of horseshoe crabs Limulus and Tachypleus. Proclotting enzyme is activated by limulus clotting factor . In peptidase family S1 (trypsin family)
References:
1.  Muta, T., Hashimoto, R., Miyata, T., Nishimura, H., Toh, Y. and Iwanaga, S. Proclotting enzyme from horseshoe crab hemocytes. cDNA cloning, disulfide locations, and subcellular localization. J. Biol. Chem. 265 (1990) 22426–22433. [PMID: 2266134]
2.  Tokunaga, F., Nakajima, H. and Iwanaga, S. Further studies on lipopolysaccharide-sensitive serine protease zymogen (factor C): its isolation from Limulus polyphemus hemocytes and identification as an intracellular zymogen activated by α-chymotrypsin, not by trypsin. J. Biochem. (Tokyo) 109 (1991) 150–157. [PMID: 2016264]
[EC 3.4.21.86 created 1993]
 
 
EC 3.4.21.87      
Transferred entry: omptin. Now EC 3.4.23.49, omptin. The enzyme is not a serine protease, as thought previously, but an aspartate protease
[EC 3.4.21.87 created 1993, deleted 2006]
 
 
EC 3.4.21.88     
Accepted name: repressor LexA
Reaction: Hydrolysis of Ala84┼Gly bond in repressor LexA
Other name(s): LexA repressor
Comments: RecA protein and single-stranded DNA are required for activity, which is attributed to a Ser/Lys dyad [2]. The LexA protein represses the SOS regulon, which regulates the genes involved in DNA repair. In the presence of single-stranded DNA, the RecA protein interacts with repressor LexA, causing it to undergo an autocatalytic cleavage which disrupts the DNA-binding part of the repressor, and inactivates it. The consequent derepression of the SOS regulon leads to DNA repair. This peptidase activity of LexA was previously attributed to the RecA protein. Type example of peptidase family S24
References:
1.  Horii, T., Ogawa, T. and Ogawa, H. Nucleotide sequence of the LexA gene of E. coli. Cell 23 (1981) 689–697. [PMID: 7013987]
2.  Slilaty, S.N. and Little, J.W. Lysine-156 and serine-119 are required for LexA repressor cleavage: a possible mechanism. Proc. Natl. Acad. Sci. USA 84 (1987) 3987–3991. [PMID: 3108885]
3.  Kim, B. and Little, J.W. LexA and CI repressors as enzymes: specific cleavage in an intermolecular reaction. Cell 73 (1993) 1165–1173. [PMID: 8513500]
4.  Little, J.W., Kim, B., Roland, K.L., Smith, M.H., Lin, L.-L. and Slilaty, S.N. Cleavage of LexA repressor. Methods Enzymol. 244 (1994) 266–284. [PMID: 7845214]
[EC 3.4.21.88 created 1995]
 
 
EC 3.4.21.89     
Accepted name: signal peptidase I
Reaction: Cleavage of hydrophobic, N-terminal signal or leader sequences
Other name(s): leader peptidase I; signal proteinase; Escherichia coli leader peptidase; eukaryotic signal peptidase; eukaryotic signal proteinase; leader peptidase; leader peptide hydrolase; leader proteinase; signal peptidase; pilin leader peptidase; SPC; prokaryotic signal peptidase; prokaryotic leader peptidase; HOSP; prokaryotic signal proteinase; propeptidase; PuIO prepilin peptidase; signal peptide hydrolase; signal peptide peptidase; signalase; bacterial leader peptidase 1; pilin leader peptidase
Comments: The enzyme is found in bacterial membranes and in chloroplast thylakoid membranes. Unaffected by inhibitors of most serine peptidases, but site-directed mutagenesis implicates a Ser/Lys catalytic dyad in activity [1,3]. Hydrolyses a single bond -Ala┼Ala- in M13 phage procoat protein, producing free signal peptide and coat protein. Formerly included in EC 3.4.99.36. Eukaryote signal peptidases that may have somewhat different specificity are known from the endoplasmic reticulum membrane [4] and mitochondrial inner membrane [2]. Type example of peptidase family S26
References:
1.  Black, M.T. Evidence that the catalytic activity of prokaryote leader peptidase depends upon the operation of a serine-lysine catalytic dyad. J. Bacteriol. 175 (1993) 4957–4961. [PMID: 8394311]
2.  Nunnari, J., Fox, T.D. and Walter, P. A mitochondrial protease with two catalytic subunits of nonoverlapping specificities. Science 262 (1993) 1997–2004. [PMID: 8266095]
3.  Tschantz, W.R., Sung, M., Delgado-Partin, V.M. and Dalbey, R.E. A serine and a lysine residue implicated in the catalytic mechanism of the Escherichia coli leader peptidase. J. Biol. Chem. 268 (1993) 27349–27354. [PMID: 8262975]
4.  Lively, M.O., Newsome, A.L. and Nusier, M. Eukaryote microsomal signal peptidases. Methods Enzymol. 244 (1994) 301–314. [PMID: 7845216]
5.  Tschantz, W.R. and Dalbey, R.E. Bacterial leader peptidase I. Methods Enzymol. 244 (1994) 285–301. [PMID: 7845215]
6.  Chaal, B.K., Mould, R.M., Barbrook, A.C., Gray, J.C. and Howe, C.J. Characterization of a cDNA encoding the thylakoidal processing peptidase from Arabidopsis thaliana. Implications for the origin and catalytic mechanism of the enzyme. J. Biol. Chem. 273 (1998) 689–692. [PMID: 9422718]
7.  Inoue, K., Baldwin, A.J., Shipman, R.L., Matsui, K., Theg, S.M. and Ohme-Takagi, M. Complete maturation of the plastid protein translocation channel requires a type I signal peptidase. J. Cell Biol. 171 (2005) 425–430. [PMID: 16275749]
[EC 3.4.21.89 created 1984 as EC 3.4.99.36, transferred 1995 to EC 3.4.21.89]
 
 
EC 3.4.21.90     
Accepted name: togavirin
Reaction: Autocatalytic release of the core protein from the N-terminus of the togavirus structural polyprotein by hydrolysis of a -Trp┼Ser- bond
Other name(s): Sindbis virus protease; Sindbis virus core protein; NsP2 proteinase
Comments: Known from the Sindbis and Semliki forest togaviruses. Once released, the core protein does not retain catalytic activity. Togavirin is the type example of peptidase family S3 and has a similar tertiary structure to chymotrypsin [3]
References:
1.  Kräusslich, H.-G. and Wimmer, E. Viral proteinases. Annu. Rev. Biochem. 57 (1988) 701–754. [PMID: 3052288]
2.  Strauss, E.G., De Groot, R.J., Levinson, R. and Strauss, J.H. Identification of the active site residues in the nsP2 proteinase of Sindbis virus. Virology 191 (1992) 932–940. [PMID: 1448929]
3.  Tong, L., Wengler, G. and Rossmann, M.G. Refined structure of Sindbis virus core protein and comparison with other chymotrypsin-like serine proteinase structures. J. Mol. Biol. 230 (1993) 228–247. [PMID: 8450538]
[EC 3.4.21.90 created 1995]
 
 
EC 3.4.21.91     
Accepted name: flavivirin
Reaction: Selective hydrolysis of -Xaa-Xaa┼Yaa- bonds in which each of the Xaa can be either Arg or Lys and Yaa can be either Ser or Ala
Other name(s): Yellow fever virus (flavivirus) protease; NS2B-3 proteinase
Comments: Known from classical flaviviruses (yellow fever, dengue fever). The functional viral peptidase is part of the NS2B protein. Catalytic His, Asp and Ser residues are arranged as in chymotrypsin, but flavivrin is the type example of peptidase family S7.
References:
1.  Chambers, T.J., Hahn, C.S., Galler, R. and Rice, C.M. Flavivirus genome organization, expression, and replication. Annu. Rev. Microbiol. 44 (1990) 649–688. [PMID: 2174669]
2.  Cahour, A., Falgout, B. and Lai, C.-J. Cleavage of the dengue virus polyprotein at the NS3/NS4A and NS4B/NS5 junctions is mediated by viral protease NS2B-NS3, whereas NS4A/NS4B may be processed by a cellular protease. J. Virol. 66 (1992) 1535–1542. [PMID: 1531368]
3.  Lin, C., Amberg, S.M., Chambers, T.J. and Rice, C.M. Cleavage at a novel site in the NS4A region by the yellow fever virus NS2B-3 proteinase is a prerequisite for processing at the downstream 4A/4B signalase site. J. Virol. 67 (1993) 2327–2335. [PMID: 8445732]
[EC 3.4.21.91 created 1995]
 
 
EC 3.4.21.92     
Accepted name: endopeptidase Clp
Reaction: Hydrolysis of proteins to small peptides in the presence of ATP and Mg2+. α-Casein is the usual test substrate. In the absence of ATP, only oligopeptides shorter than five residues are hydrolysed (such as succinyl-Leu-Tyr┼NHMec; and Leu-Tyr-Leu┼Tyr-Trp, in which cleavage of the -Tyr┼Leu- and -Tyr┼Trp bonds also occurs)
Other name(s): endopeptidase Ti; caseinolytic protease; protease Ti; ATP-dependent Clp protease; endopeptidase Ti; caseinolytic protease; ClpP; Clp protease
Comments: An enzyme from bacteria that contains subunits of two types, ClpP, with peptidase activity, and ClpA, with ATPase activity. The ClpAP complex, which displays ATP-dependent endopeptidase activity, has the composition (ClpP14ClpA6)2 [4]. ClpP is the type example of peptidase family S14
References:
1.  Gottesman, S., Clark, W.P. and Maurizi, M.R. The ATP-dependent Clp protease of Escherichia coli. Sequence of clpA and identification of a Clp-specific substrate. J. Biol. Chem. 265 (1990) 7886–7893. [PMID: 2186030]
2.  Maurizi, M.R., Clark, W.P., Katayama, Y., Rudikoff, S., Pumphrey, J., Bowers, B. and Gottesman, S. Sequence and structure of Clp P, the proteolytic component of the ATP-dependent Clp protease of Escherichia coli. J. Biol. Chem. 265 (1990) 12536–12545. [PMID: 2197275]
3.  Maurizi, M.R., Thompson, M.W., Singh, S.K. and Kim, S.-H. Endopeptidase Clp: the ATP-dependent Clp protease from Escherichia coli. Methods Enzymol. 244 (1994) 314–331. [PMID: 7845217]
4.  Kessel, M. , Maurizi,M.R., Kim, B., Kocsis, E., Trus, B., Singh, S.K. and Steven, A.C. Homology in structural organization between E. coli ClpAP protease and the eukaryotic 26 S proteasome. J. Mol. Biol. 250 (1995) 587–594. [PMID: 7623377]
[EC 3.4.21.92 created 1996]
 
 
EC 3.4.21.93     
Accepted name: proprotein convertase 1
Reaction: Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg┼ bonds
Other name(s): prohormone convertase 3; neuroendocrine convertase 1; PC1
Comments: A Ca2+-dependent enzyme, maximally active at about pH 5.5. Substrates include pro-opiomelanocortin, prorenin, proenkephalin, prodynorphin, prosomatostatin and proinsulin. Unlike prohormone convertase 2, does not hydrolyse proluteinizing-hormone-releasing-hormone. Unusually, processing of prodynorphin occurs at a bond in which P2 is Thr. Present in the regulated secretory pathway of neuroendocrine cells, commonly acting co-operatively with prohormone convertase 2. In peptidase family S8 (subtilisin family)
References:
1.  Seidah, N.G., Gaspar, L., Mion, P., Marcinkiewicz, M., Mbikay, M. and Chrétien, M. cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases. DNA Cell Biol. 9 (1990) 415–424. [PMID: 2169760]
2.  Smeekens, S.P., Avruch, A.S., LaMendola, J., Chan, S.J. and Steiner, D.F. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proc. Natl. Acad. Sci. USA 88 (1991) 340–344. [PMID: 1988934]
3.  Steiner, D.F., Smeekens, S.P., Ohagi, S. and Chan, S.J. The new enzymology of precursor processing endoproteases. J. Biol. Chem. 267 (1992) 23435–23438. [PMID: 1429684]
4.  Seidah, N.G. and Chrétien, M. Pro-protein convertases of the subtilisin/kexin family. Methods Enzymol. 244 (1994) 175–188. [PMID: 7845206]
5.  Jean, F., Basak, A., Dimaio, J., Seidah, N.G. and Lazure, C. An internally quenched fluorogenic substrate of prohormone convertase 1 and furin leads to a potent prohormone convertase inhibitor. Biochem. J. 307 (1995) 689–695. [PMID: 7741698]
[EC 3.4.21.93 created 1996]
 
 
EC 3.4.21.94     
Accepted name: proprotein convertase 2
Reaction: Release of protein hormones and neuropeptides from their precursors, generally by hydrolysis of -Lys-Arg┼ bonds
Other name(s): neuroendocrine convertase 2; PC2
Comments: A Ca2+-dependent enzyme, maximally active at about pH 5.5. Specificity is broader than that of prohormone convertase 1. Substrates include pro-opiomelanocortin, proenkephalin, prodynorphin, proglucagon, proinsulin and proluteinizing-hormone-releasing-hormone. Does not hydrolyse prorenin or prosomatostatin, however. Unusually, processing of prodynorphin occurs at a bond in which P2 is Thr. Present in the regulated secretory pathway of neuroendocrine cells, commonly acting co-operatively with prohormone convertase 1. In peptidase family S8 (subtilisin family)
References:
1.  Seidah, N.G., Gaspar, L., Mion, P., Marcinkiewicz, M., Mbikay, M. and Chrétien, M. cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases. DNA Cell Biol. 9 (1990) 415–424. [PMID: 2169760]
2.  Smeekens, S.P. and Steiner, D.F. Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J. Biol. Chem. 265 (1990) 2997–3000. [PMID: 2154467]
3.  Rouillé, Y., Westermark, G., Martin, S.K. and Steiner, D.F. Proglucagon is processed to glucagon by prohormone convertase PC2 in alphaTC1-6 cells. Proc. Natl. Acad. Sci. USA 91 (1994) 3242–3246. [PMID: 8159732]
4.  Seidah, N.G. and Chrétien, M. Pro-protein convertases of the subtilisin/kexin family. Methods Enzymol. 244 (1994) 175–188. [PMID: 7845206]
[EC 3.4.21.94 created 1996]
 
 
EC 3.4.21.95     
Accepted name: snake venom factor V activator
Reaction: Fully activates human clotting factor V by a single cleavage at the Trp-Tyr-Leu-Arg1545┼Ser-Asn-Asn-Gly bond. Cattle, but not rabbit, factor V is cleaved, and no other proteins of the clotting system are attacked. Esterase activity is observed on Bz-Arg-OEt and Tos-Arg-OMe, and amidase activity on Phe-pipecolyl-Arg-NHPhNO2
Comments: Known from venom of Vipera russelli. Inhibited by di-isopropyl fluorophosphate, unlike the metallopeptidase russellysin (EC 3.4.24.58) that is specific for factor X [1]. In peptidase family S1 (trypsin family) [2].
References:
1.  Kisiel, W. and Canfield, W. M. Snake venom proteases that activate blood-coagulation factor V. Methods Enzymol. 80 (1981) 275–285. [PMID: 7043192]
2.  Tokunaga, F., Nagasawa, K., Tamura, S., Miyata, T., Iwanaga, S. and Kisiel, W. The factor V-activating enzyme (RVV-V) from Russell's viper venom. Identification of isoproteins RVV-Vα, -Vβ and -Vγ and their complete amino acid sequences. J. Biol. Chem. 263 (1988) 17417–17481. [PMID: 3053712]
[EC 3.4.21.95 created 1997]
 
 
EC 3.4.21.96     
Accepted name: lactocepin
Reaction: Endopeptidase activity with very broad specificity, although some subsite preferences have been noted, e.g. large hydrophobic residues in the P1 and P4 positions, and Pro in the P2 position [1,2]. Best known for its action on caseins, although it has been shown to hydrolyse hemoglobin and oxidized insulin B chain
Other name(s): CEP; extracellular lactococcal proteinase; lactococcal cell wall-associated proteinase; lactococcal cell envelope-associated proteinase; lactococcal proteinase; PrtP
Comments: Associated with the cell envelope of Lactococcus lactis and attached via a C-terminal membrane anchor sequence. Responsible for the hydrolysis of casein in milk and the provision of peptides essential to cell growth. Important in cheese making and the production of lactic casein, being required for rapid growth to high cell densities with concomitant production of adequate levels of lactic acid. Specificity differences between lactocepins from different starter strains may be partly responsible for imparting different flavour qualities to cheese [4]. In peptidase family S8 (subtilisin family)
References:
1.  Visser, S., Robben, A.J.P.M. and Slangen, C.J. Specificity of a cell-envelope-located proteinase (PIII-type) from Lactococcus lactis subsp. cremoris AM1 in its action on bovine β-casein. Appl. Microbiol. Biotechnol. 35 (1991) 477–483. [PMID: 1367552]
2.  Monnet, V., Ley, J.P. and Gonzalez, S. Substrate specificity of the cell envelope-located proteinase of Lactococcus lactis subsp. lactis NCDO763. Int. J. Biochem. 24 (1992) 707–718. [PMID: 1592148]
3.  Exterkate, F.A., Alting, A.C. and Bruinenberg, P.G. Diversity of cell envelope proteinase specificity among strains of Lactococcus lactis and its relationship to charge characteristics of the substrate-binding region. Appl. Environ. Microbiol. 59 (1993) 3640–3647. [PMID: 8285671]
4.  Pritchard, G.G. and Coolbear, T. The physiology and biochemistry of the proteolytic system in lactic acid bacteria. FEMS Microbiol. Rev. 12 (1993) 179–206. [PMID: 8398214]
[EC 3.4.21.96 created 1997]
 
 
EC 3.4.21.97     
Accepted name: assemblin
Reaction: Cleaves -Ala┼Ser- and -Ala┼Ala- bonds in the scaffold protein
Comments: Involved in the breakdown of the scaffold protein during the late stages of assembly of the herpes-virus virion. Inhibited by diisopropyl fluorophosphate. Type example of peptidase family S21. Catalytic residues are His, Ser, His, a combination not known for any other peptidase, and the protein fold also is unique. Known from herpes viruses of several types, cytomegalovirus, Epstein-Barr virus and human herpesvirus 3
References:
1.  Chen, P., Tsuge, H., Almassy, R.J., Gribskov, C.L., Katoh, S., Vanderpool, D.L., Margosiak, S.A., Pinko, C., Matthews, D.A. and Kan, C.C. Structure of the human cytomegalovirus protease catalytic domain reveals a novel serine protease fold and catalytic triad. Cell 86 (1996) 477–483. [PMID: 8797829]
2.  Darke, P.L. Herpesvirus assemblin. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 470–472.
[EC 3.4.21.97 created 2000]
 
 
EC 3.4.21.98     
Accepted name: hepacivirin
Reaction: Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1′
Other name(s): Cpro-2; hepatitis C virus NS3 serine proteinase; NS3-4A serine proteinase complex
Comments: Encoded by the genome of the viruses of the hepatitis C group, and contributes to the maturation of the precursor polyproteins. The enzyme is greatly activated by binding of the 54-residue NS4A ’cofactor’ protein also derived from the viral polyprotein. Type example of peptidase family S29. The crystallographic structure shows a chymotrypsin-like fold.
References:
1.  Kim, J.L., Morgenstern, K.A., Lin, C., Fox, T., Dwyer, M.D., Landro, J.A., Chambers, S.P., Markland, W., Lepre, C.A., O'Malley, E.T., Harbeson, S.L., Rice, C.M., Murcko, M.A., Caron, P.R. and Thomson, J.A. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87 (1996) 343–355. [PMID: 8861917]
2.  Rice, C.M. Hepatitis C virus polyprotein peptidase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 272–277.
[EC 3.4.21.98 created 2000]
 
 
EC 3.4.21.99     
Accepted name: spermosin
Reaction: Hydrolyses arginyl bonds, preferably with Pro in the P2 position
Comments: The enzyme from the ascidian (Prochordate) Halocynthia roretzi is localized in the sperm head, and released during sperm activation. A proline-rich region is involved in binding to the vitelline coat of the egg. Belongs in peptidase family S1 (trypsin family).
References:
1.  Sawada, H., Yokosawa, H. and Ishii, S. Purification and characterization of two types of trypsin-like enzymes from sperm of the ascidian (Prochordata) Halocynthia roretzi. Evidence for the presence of spermosin, a novel acrosin-like enzyme. J. Biol. Chem. 259 (1984) 2900–2904. [PMID: 6365918]
2.  Sawada, H., Yokosawa, H., Someno, T., Saino, T. and Ishii, S. Evidence for the participation of two sperm proteases, spermosin and acrosin, in fertilization of the ascidian, Halocynthia roretzi: inhibitory effects of leupeptin analogs on enzyme activities and fertilization. Dev. Biol. 105 (1984) 246–249. [PMID: 6381175]
3.  Sawada, H., Iwasaki, K., Kihara-Negishi, F., Ariga, H. and Yokosawa, H. Localization, expression, and the role in fertilization of spermosin, an ascidian sperm trypsin-like protease. Biochem. Biophys. Res. Commun. 222 (1996) 499–504. [PMID: 8670234]
4.  Sawada, H. and Someno, T. Substrate specificity of ascidian sperm trypsin-like proteases, spermosin and acrosin. Mol. Reprod. Dev. 45 (1996) 240–243. [PMID: 8914083]
[EC 3.4.21.99 created 2001]
 
 
EC 3.4.21.100     
Accepted name: sedolisin
Reaction: Hydrolysis of the B chain of insulin at -Glu13┼Ala-, -Leu15┼Tyr- and -Phe25┼Tyr-, and angiotensin I at -Tyr4┼Ile-. A good synthetic substrate is Lys-Pro-Ile-Glu-Phe┼Phe(NO2)-Arg-Leu.
Other name(s): Pseudomonas sp. pepstatin-insensitive carboxyl proteinase; pseudomonapepsin; pseudomonalisin; sedolysin
Comments: An enzyme secreted by Pseudomonas sp. No. 101. Optimum pH is 4. It is distinguished from xanthomonapepsin by its insensitivity to EPNP and from scytalidopepsin B by this property and by its unrelated amino-acid sequence. Inhibited by tyrostatin, a peptide aldehyde [2]. Type example of peptidase family S53.
References:
1.  Oda, K., Sugitani, M., Fukuhara, K. and Murao, S. Purification and properties of a pepstatin-insensitive carboxyl proteinase from a Gram-negative bacterium. Biochim. Biophys. Acta 923 (1987) 463–469. [PMID: 3548827]
2.  Oda, K., Nakatani, H. and Dunn, B.M. Substrate specificity and kinetic properties of pepstatin-insensitive carboxyl proteinase from Pseudomonas sp. No. 101. Biochim. Biophys. Acta 1120 (1992) 208–214. [PMID: 1562589]
3.  Wlodawer, A., Li, M., Dauter, Z., Gustchina, A., Uchida, K., Oyama, H., Dunn, B.M. and Oda, K. Carboxyl proteinase from Pseudomonas defines a novel family of subtilisin-like enzymes. Nat. Struct. Biol. 8 (2001) 442–446. [PMID: 11323721]
4.  Wlodawer, A., Li, M., Gustchina, A., Oyama, H., Dunn, B.M. and Oda, K. Structural and enzymatic properties of the sedolisin family of serine-carboxyl peptidases. Acta Biochim. Pol. 50 (2003) 81–102. [PMID: 12673349]
[EC 3.4.21.100 created 1995 as EC 3.4.23.37, transferred 2001 to EC 3.4.21.100, modified 2003]
 
 
EC 3.4.21.101     
Accepted name: xanthomonalisin
Reaction: Cleavage of casein
Other name(s): Xanthomonas aspartic proteinase; xanthomonapepsin; sedolisin-B
Comments: Secreted by the bacterium Xanthomonas sp. Belongs in peptidase family S53.
References:
1.  Oda, K., Nakazima, T., Terashita, T., Suzuki, K. and Murao, S. Purification and properties of an S-PI(pepstatin Ac)-insensitive carboxyl proteinase from a Xanthomonas sp. bacterium. Agric. Biol. Chem. 51 (1987) 3073–3080.
2.  Wlodawer, A., Li, M., Gustchina, A., Oyama, H., Dunn, B.M. and Oda, K. Structural and enzymatic properties of the sedolisin family of serine-carboxyl peptidases. Acta Biochim. Pol. 50 (2003) 81–102. [PMID: 12673349]
[EC 3.4.21.101 created 1995 as EC 3.4.23.33, transferred 2001 to EC 3.4.21.101, modified 2003]
 
 
EC 3.4.21.102     
Accepted name: C-terminal processing peptidase
Reaction: The enzyme shows specific recognition of a C-terminal tripeptide, Xaa-Yaa-Zaa, in which Xaa is preferably Ala or Leu, Yaa is preferably Ala or Tyr, and Zaa is preferably Ala, but then cleaves at a variable distance from the C-terminus. A typical cleavage is -Ala-Ala┼Arg-Ala-Ala-Lys-Glu-Asn-Tyr-Ala-Leu-Ala-Ala. In the plant chloroplast, the enzyme removes the C-terminal extension of the D1 polypeptide of photosystem II
Other name(s): CtpA gene product (Synechocystis sp.); photosystem II D1 protein processing peptidase; protease Re; tail-specific protease; Tsp protease
Comments: Proteolytic processing of the D1 protein of photosystem II is necessary to allow the light-driven assembly of the tetranuclear manganese cluster, which is responsible for photosynthetic water oxidation. The recognition of the substrate is mediated by a PDZ domain, a small protein module that promotes protein-protein interactions by binding to internal or C-terminal sequences of their partner proteins. Type example of peptidase family S41.
References:
1.  Keiler, K.C. and Sauer, R.T. Tsp protease. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 460–461.
2.  Beebe, K.D., Shin, J.N., Peng, J., Chaudhury, C., Khera, J. and Pei, D.H. Substrate recognition through a PDZ domain in tail-specific protease. Biochemistry 39 (2000) 3149–3155. [PMID: 10715137]
3.  Liao, D.I., Qian, J., Chisholm, D.A., Jordan, D.B. and Diner, B.A. Crystal structures of the photosystem II D1 C-terminal processing protease. Nat. Struct. Biol. 7 (2000) 749–753. [PMID: 10966643]
[EC 3.4.21.102 created 2001]
 
 
EC 3.4.21.103     
Accepted name: physarolisin
Reaction: Milk clotting activity. Preferential cleavage of Gly8┼Ser in B chain of insulin most rapidly, followed by Leu11┼Val, Cys(SO3H)19┼Gly and Phe24┼Phe. No action on Ac-Phe-Tyr(I)2.
Other name(s): Dictyostelium discoideum aspartic proteinase; Dictyostelium discoideum aspartic proteinase E; Physarum flavicomum aspartic proteinase; Physarum polycephalum acid proteinase; Physarum aspartic proteinase; physaropepsin
Comments: Belongs in peptidase family S53. From the slime mold Physarum polycephalum. Is not inhibited by pepstatin, but is blocked by methyl 2-diazoacetamidohexanoate. Closely similar enzymes are found in Dictyostelium discoideum and P. flavicomum. Formerly included in EC 3.4.23.6.
References:
1.  Henney, H.R. and Tavana, G. Purification and some properties of an intracellular acid (carboxyl) proteinase from differentiating haploid cells of Physarum flavicomum. Exp. Mycol. 6 (1982) 161–170.
2.  Murakami-Murofushi, K., Hiratsuka, A. and Ohta, J. A novel acid protease from haploid amoebae of Physarum polycephalum, and its changes during mating and subsequent differentiation into diploid plasmodia. Cell Struct. Funct. 9 (1984) 311–315.
3.  North, M.J. and Whyte, A. Purification and characterization of two acid proteinases from Dictyostelium discoideum. J. Gen. Microbiol. 130 (1984) 123–134.
4.  Wlodawer, A., Li, M., Gustchina, A., Oyama, H., Dunn, B.M. and Oda, K. Structural and enzymatic properties of the sedolisin family of serine-carboxyl peptidases. Acta Biochim. Pol. 50 (2003) 81–102. [PMID: 12673349]
5.  Nishii, W., Ueki, T., Miyashita, R., Kojima, M., Kim, Y.T., Sasaki, N., Murakami-Murofushi, K. and Takahashi, K. Structural and enzymatic characterization of physarolisin (formerly physaropepsin) proves that it is a unique serine-carboxyl proteinase. Biochem. Biophys. Res. Commun. 301 (2003) 1023–1029. [PMID: 12589815]
[EC 3.4.21.103 created 1992 as EC 3.4.23.27 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992), transferred 2003 to EC 3.4.21.103]
 
 
EC 3.4.21.104     
Accepted name: mannan-binding lectin-associated serine protease-2
Reaction: Selective cleavage after Arg223 in complement component C2 (-Ser-Leu-Gly-Arg┼Lys-Ile-Gln-Ile) and after Arg76 in complement component C4 (-Gly-Leu-Gln-Arg┼Ala-Leu-Glu-Ile)
Other name(s): MASP-2; MASP2; MBP-associated serine protease-2; mannose-binding lectin-associated serine protease-2; p100; mannan-binding lectin-associated serine peptidase 2
Comments: Mannan-binding lectin (MBL) recognizes patterns of neutral carbohydrates, such as mannose and N-acetylglucosamine, on a wide range of microbial surfaces and is able to initiate activation of the lectin pathway of complement [7]. This enzyme displays C1s-like esterolytic activity (cf. EC 3.4.21.42, complement subcomponent C1s). It also cleaves C4 and C2 with efficiencies that are relatively higher than those of EC 3.4.21.42 [3]. Belongs in peptidase family S1A.
References:
1.  Matsushita, M. and Fujita, T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J. Exp. Med. 176 (1992) 1497–1502. [PMID: 1460414]
2.  Thiel, S., Vorup-Jensen, T., Stover, C.M., Schwaeble, W., Laursen, S.B., Poulsen, K., Willis, A.C., Eggleton, P., Hansen, S., Holmskov, U., Reid, K.B. and Jensenius, J.C. A second serine protease associated with mannan-binding lectin that activates complement. Nature 386 (1997) 506–510. [PMID: 9087411]
3.  Rossi, V., Cseh, S., Bally, I., Thielens, N.M., Jensenius, J.C. and Arlaud, G.J. Substrate specificities of recombinant mannan-binding lectin-associated serine proteases-1 and -2. J. Biol. Chem. 276 (2001) 40880–40887. [PMID: 11527969]
4.  Ambrus, G., Gal, P., Kojima, M., Szilagyi, K., Balczer, J., Antal, J., Graf, L., Laich, A., Moffatt, B.E., Schwaeble, W., Sim, R.B. and Zavodszky, P. Natural substrates and inhibitors of mannan-binding lectin-associated serine protease-1 and -2: a study on recombinant catalytic fragments. J. Immunol. 170 (2003) 1374–1382. [PMID: 12538697]
5.  Harmat, V., Gal, P., Kardos, J., Szilagyi, K., Ambrus, G., Vegh, B., Naray-Szabo, G. and Zavodszky, P. The structure of MBL-associated serine protease-2 reveals that identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions. J. Mol. Biol. 342 (2004) 1533–1546. [PMID: 15364579]
6.  Chen, C.B. and Wallis, R. Two mechanisms for mannose-binding protein modulation of the activity of its associated serine proteases. J. Biol. Chem. 279 (2004) 26058–26065. [PMID: 15060079]
7.  Teillet, F., Dublet, B., Andrieu, J.P., Gaboriaud, C., Arlaud, G.J. and Thielens, N.M. The two major oligomeric forms of human mannan-binding lectin: chemical characterization, carbohydrate-binding properties, and interaction with MBL-associated serine proteases. J. Immunol. 174 (2005) 2870–2877. [PMID: 15728497]
[EC 3.4.21.104 created 2005]
 
 
EC 3.4.21.105     
Accepted name: rhomboid protease
Reaction: Cleaves type-1 transmembrane domains using a catalytic dyad composed of serine and histidine that are contributed by different transmembrane domains
Comments: These endopeptidases are multi-spanning membrane proteins. Their catalytic site is embedded within the membrane and they cleave type-1 transmembrane domains. A catalytic dyad is involved in proteolysis rather than a catalytic triad, as was thought previously [14]. They are important for embryo development in Drosophila melanogaster. Rhomboid is a key regulator of EGF receptor signalling and is responsible for cleaving Spitz, the main ligand of the Drosophila EGF receptor pathway. Belongs in peptidase family S54. Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite. Rhomboids are widely conserved from bacteria to archaea to humans [9,13].
References:
1.  Urban, S. and Wolfe, M.S. Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc. Natl. Acad. Sci. USA 102 (2005) 1883–1888. [PMID: 15684070]
2.  Brossier, F., Jewett, T.J., Sibley, L.D. and Urban, S. A spatially localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma. Proc. Natl. Acad. Sci. USA 102 (2005) 4146–4151. [PMID: 15753289]
3.  Herlan, M., Bornhovd, C., Hell, K., Neupert, W. and Reichert, A.S. Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor. J. Cell Biol. 165 (2004) 167–173. [PMID: 15096522]
4.  Pascall, J.C. and Brown, K.D. Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL 2. Biochem. Biophys. Res. Commun. 317 (2004) 244–252. [PMID: 15047175]
5.  Sik, A., Passer, B.J., Koonin, E.V. and Pellegrini, L. Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pβ, a nuclear-targeted peptide. J. Biol. Chem. 279 (2004) 15323–15329. [PMID: 14732705]
6.  Urban, S. and Freeman, M. Substrate specificity of Rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain. Mol. Cell 11 (2003) 1425–1434. [PMID: 12820957]
7.  Herlan, M., Vogel, F., Bornhovd, C., Neupert, W. and Reichert, A.S. Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. J. Biol. Chem. 278 (2003) 27781–27788. [PMID: 12707284]
8.  McQuibban, G.A., Saurya, S. and Freeman, M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423 (2003) 537–541. [PMID: 12774122]
9.  Koonin, E.V., Makarova, K.S., Rogozin, I.B., Davidovic, L., Letellier, M.C. and Pellegrini, L. The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers. Genome Biol. 4 (2003) R19. [PMID: 12620104]
10.  Urban, S. and Freeman, M. Intramembrane proteolysis controls diverse signalling pathways throughout evolution. Curr. Opin. Genet. Dev. 12 (2002) 512–518. [PMID: 12200155]
11.  Urban, S., Schlieper, D. and Freeman, M. Conservation of intramembrane proteolytic activity and substrate specificity in prokaryotic and eukaryotic Rhomboids. Curr. Biol. 12 (2002) 1507–1512. [PMID: 12225666]
12.  Urban, S., Lee, J.R. and Freeman, M. A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF-like ligands. EMBO J. 21 (2002) 4277–4286. [PMID: 12169630]
13.  Urban, S., Lee, J.R. and Freeman, M. Drosophila Rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107 (2001) 173–182. [PMID: 11672525]
14.  Lemberg, M.K., Menendez, J., Misik, A., Garcia, M., Koth, C.M. and Freeman, M. Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. EMBO J. 24 (2005) 464–472. [PMID: 15616571]
15.  Wang, Y., Zhang, Y. and Ha, Y. Crystal structure of a rhomboid family intramembrane protease. Nature 444 (2006) 179–180. [PMID: 17051161]
[EC 3.4.21.105 created 2005]
 
 
EC 3.4.21.106     
Accepted name: hepsin
Reaction: Cleavage after basic amino-acid residues, with Arg strongly preferred to Lys
Comments: This type-II membrane-associated serine peptidase has been implicated in cell growth and development [1,3]. The enzyme has been shown to activate blood coagulation factor VII by cleavage of the Arg152┼Ile153 peptide bound in BHK cells, thus indicating a possible role in the initiation of blood coagulation [2]. There is no cleavage after aromatic or aliphatic residues [1]. The occupancy of the S2 site is an absolute requirement for catalysis and a basic residue at that site is preferred to an aliphatic residue. The nature of the residue at S3 also affects hydrolysis, with Gln being much more favourable than Ala [1]. Belongs in peptidase family S1A.
References:
1.  Zhukov, A., Hellman, U. and Ingelman-Sundberg, M. Purification and characterization of hepsin from rat liver microsomes. Biochim. Biophys. Acta 1337 (1997) 85–95. [PMID: 9003440]
2.  Kazama, Y., Hamamoto, T., Foster, D.C. and Kisiel, W. Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation. J. Biol. Chem. 270 (1995) 66–72. [PMID: 7814421]
3.  Torres-Rosado, A., O'Shea, K.S., Tsuji, A., Chou, S.H. and Kurachi, K. Hepsin, a putative cell-surface serine protease, is required for mammalian cell growth. Proc. Natl. Acad. Sci. USA 90 (1993) 7181–7185. [PMID: 8346233]
[EC 3.4.21.106 created 2006]
 
 
EC 3.4.21.107     
Accepted name: peptidase Do
Reaction: Acts on substrates that are at least partially unfolded. The cleavage site P1 residue is normally between a pair of hydrophobic residues, such as Val┼Val
Other name(s): DegP; DegP protease; HtrA; high temperature requirement protease A; HrtA heat shock protein; protease Do; Do protease
Comments: This serine endopeptidase is essential for the clearance of denatured or aggregated proteins from the inner-membrane and periplasmic space in Escherichia coli. Natural substrates of the enzyme include colicin A lysis protein, pilin subunits and MalS from E. coli [3]. The enzyme has weak peptidase activity with casein and other non-native substrates [3]. The peptidase acts as a chaperone at low temperatures but switches to a peptidase (heat shock protein) at higher temperatures [1,6]. Molecular chaperones and peptidases control the folded state of proteins by recognizing hydrophobic stretches of polypeptide that become exposed by misfolding or unfolding. They then bind these hydrophobic substrates to prevent aggregation or assist in protein refolding. If attempts at refolding fail, then irreversibly damaged proteins are degraded by peptidases such as this enzyme [6]. Belongs in peptidase family S1C.
References:
1.  Lipinska, B., Zylicz, M. and Georgopoulos, C. The HtrA (DegP) protein, essential for Escherichia coli survival at high temperatures, is an endopeptidase. J. Bacteriol. 172 (1990) 1791–1797. [PMID: 2180903]
2.  Seol, J.H., Woo, S.K., Jung, E.M., Yoo, S.J., Lee, C.S., Kim, K.J., Tanaka, K., Ichihara, A., Ha, D.B. and Chung, C.H. Protease Do is essential for survival of Escherichia coli at high temperatures: its identity with the htrA gene product. Biochem. Biophys. Res. Commun. 176 (1991) 730–736. [PMID: 2025286]
3.  Jones, C.H., Dexter, P., Evans, A.K., Liu, C., Hultgren, S.J. and Hruby, D.E. Escherichia coli DegP protease cleaves between paired hydrophobic residues in a natural substrate: the PapA pilin. J. Bacteriol. 184 (2002) 5762–5771. [PMID: 12270835]
4.  Swamy, K.H., Chung, C.H. and Goldberg, A.L. Isolation and characterization of protease Do from Escherichia coli, a large serine protease containing multiple subunits. Arch. Biochem. Biophys. 224 (1983) 543–554. [PMID: 6347072]
5.  Pallen, M.J. and Wren, B.W. The HtrA family of serine proteases. Mol. Microbiol. 26 (1997) 209–221. [PMID: 9383148]
6.  Krojer, T., Garrido-Franco, M., Huber, R., Ehrmann, M. and Clausen, T. Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine. Nature 416 (2002) 455–459. [PMID: 11919638]
[EC 3.4.21.107 created 2006]
 
 
EC 3.4.21.108     
Accepted name: HtrA2 peptidase
Reaction: Cleavage of non-polar aliphatic amino-acids at the P1 position, with a preference for Val, Ile and Met. At the P2 and P3 positions, Arg is selected most strongly with a secondary preference for other hydrophilic residues
Other name(s): high temperature requirement protein A2; HtrA2; Omi stress-regulated endoprotease; serine proteinase OMI; HtrA2 protease; OMI/HtrA2 protease; HtrA2/Omi; Omi/HtrA2
Comments: This enzyme is upregulated in mammalian cells in response to stress induced by both heat shock and tunicamycin treatment [4]. It can induce apoptosis in a caspase-independent manner through its peptidase activity and in a caspase-dependent manner by disrupting the interaction between caspase and the inhibitor of apoptosis (IAP) [3]. Belongs in peptidase family S1C.
References:
1.  Srinivasula, S.M., Gupta, S., Datta, P., Zhang, Z., Hegde, R., Cheong, N., Fernandes-Alnemri, T. and Alnemri, E.S. Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2. J. Biol. Chem. 278 (2003) 31469–31472. [PMID: 12835328]
2.  Savopoulos, J.W., Carter, P.S., Turconi, S., Pettman, G.R., Karran, E.H., Gray, C.W., Ward, R.V., Jenkins, O. and Creasy, C.L. Expression, purification, and functional analysis of the human serine protease HtrA2. Protein. Expr. Purif. 19 (2000) 227–234. [PMID: 10873535]
3.  Martins, L.M., Turk, B.E., Cowling, V., Borg, A., Jarrell, E.T., Cantley, L.C. and Downward, J. Binding specificity and regulation of the serine protease and PDZ domains of HtrA2/Omi. J. Biol. Chem. 278 (2003) 49417–49427. [PMID: 14512424]
4.  Gray, C.W., Ward, R.V., Karran, E., Turconi, S., Rowles, A., Viglienghi, D., Southan, C., Barton, A., Fantom, K.G., West, A., Savopoulos, J., Hassan, N.J., Clinkenbeard, H., Hanning, C., Amegadzie, B., Davis, J.B., Dingwall, C., Livi, G.P. and Creasy, C.L. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur. J. Biochem. 267 (2000) 5699–5710. [PMID: 10971580]
5.  Li, W., Srinivasula, S.M., Chai, J., Li, P., Wu, J.W., Zhang, Z., Alnemri, E.S. and Shi, Y. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nat. Struct. Biol. 9 (2002) 436–441. [PMID: 11967569]
[EC 3.4.21.108 created 2006]
 
 
EC 3.4.21.109     
Accepted name: matriptase
Reaction: Cleaves various synthetic substrates with Arg or Lys at the P1 position and prefers small side-chain amino acids, such as Ala and Gly, at the P2 position
Other name(s): serine protease 14; membrane-type serine protease 1; MT-SP1; prostamin; serine protease TADG-15; tumor-associated differentially-expressed gene 15 protein; ST14; breast cancer 80 kDa protease; epithin; serine endopeptidase SNC19
Comments: This trypsin-like integral-membrane serine peptidase has been implicated in breast cancer invasion and metastasis [1,2]. The enzyme can activate hepatocyte growth factor/scattering factor (HGF/SF) by cleavage of the two-chain form at an Arg residue to give active α- and β-HGF, but It does not activate plasminogen, which shares high homology with HGF [1]. The enzyme can also activate urokinase plasminogen activator (uPA), which initiates the matrix-degrading peptidase cascade [1,2]. Belongs in peptidase family S1A.
References:
1.  Lee, S.L., Dickson, R.B. and Lin, C.Y. Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. J. Biol. Chem. 275 (2000) 36720–36725. [PMID: 10962009]
2.  Lin, C.Y., Anders, J., Johnson, M., Sang, Q.A. and Dickson, R.B. Molecular cloning of cDNA for matriptase, a matrix-degrading serine protease with trypsin-like activity. J. Biol. Chem. 274 (1999) 18231–18236. [PMID: 10373424]
[EC 3.4.21.109 created 2006]
 
 
EC 3.4.21.110     
Accepted name: C5a peptidase
Reaction: The primary cleavage site is at His67┼Lys68 in human C5a with a minor secondary cleavage site at Ala58┼Ser59
Other name(s): streptococcal C5a peptidase; ScpA; ScpB; SCPA
Comments: This enzyme is a surface-associated subtilisin-like serine peptidase with very specific substrate specificity. Virulent strains of streptococci, including Streptococcus pyogenes, can evade human detection and phagocytosis by destroying the complement chemotaxin C5a. Cleavage of human C5a by this enzyme reduces the ability of C5a to bind receptors on the surface of polymorphonuclear neutrophil leukocytes (PMNLs) and thereby abolishes its chemotactic properties [1,4]. Belongs in peptidase family S8A.
References:
1.  Wexler, D.E., Chenoweth, D.E. and Cleary, P.P. Mechanism of action of the group A streptococcal C5a inactivator. Proc. Natl. Acad. Sci. USA 82 (1985) 8144–8148. [PMID: 3906656]
2.  Bohnsack, J.F., Mollison, K.W., Buko, A.M., Ashworth, J.C. and Hill, H.R. Group B streptococci inactivate complement component C5a by enzymic cleavage at the C-terminus. Biochem. J. 273 (1991) 635–640. [PMID: 1996961]
3.  Cleary, P.P., Prahbu, U., Dale, J.B., Wexler, D.E. and Handley, J. Streptococcal C5a peptidase is a highly specific endopeptidase. Infect. Immun. 60 (1992) 5219–5223. [PMID: 1452354]
4.  Anderson, E.T., Wetherell, M.G., Winter, L.A., Olmsted, S.B., Cleary, P.P. and Matsuka, Y.V. Processing, stability, and kinetic parameters of C5a peptidase from Streptococcus pyogenes. Eur. J. Biochem. 269 (2002) 4839–4851. [PMID: 12354115]
5.  Stafslien, D.K. and Cleary, P.P. Characterization of the streptococcal C5a peptidase using a C5a-green fluorescent protein fusion protein substrate. J. Bacteriol. 182 (2000) 3254–3258. [PMID: 10809707]
6.  Terao, Y., Yamaguchi, M., Hamada, S. and Kawabata, S. Multifunctional glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes is essential for evasion from neutrophils. J. Biol. Chem. 281 (2006) 14215–14223. [PMID: 16565520]
[EC 3.4.21.110 created 2006]
 
 
EC 3.4.21.111     
Accepted name: aqualysin 1
Reaction: Exhibits low specificity towards esters of amino acids with small hydrophobic or aromatic residues at the P1 position
Other name(s): caldolysin
Comments: This enzyme from the extreme thermophile, Thermus aquaticus, is an alkaline serine peptidase. It has three subsites, S1, S2, and S3, in the substrate binding site. The preferred amino acids at the S1 site are Ala and Phe, at the S2 site are Ala and norleucine and at the S3 site are Phe and Ile [3]. These specificities are similar to those of EC 3.4.21.64 (peptidase K) and EC 3.4.21.62 (subtilisin BPN′) [3]. The enzyme displays broad specificity for cleavage of insulin B-chain and hydrolyses elastin substrates such as succinyl-(Ala)n-p-nitroanilide (n = 1,2,3) and some peptide esters [1,3]. Belongs in peptidase family S8A.
References:
1.  Matsuzawa, H., Tokugawa, K., Hamaoki, M., Mizoguchi, M., Taguchi, H., Terada, I., Kwon, S.T. and Ohta, T. Purification and characterization of aqualysin I (a thermophilic alkaline serine protease) produced by Thermus aquaticus YT-1. Eur. J. Biochem. 171 (1988) 441–447. [PMID: 3162211]
2.  Tanaka, T., Matsuzawa, H., Kojima, S., Kumagai, I., Miura, K. and Ohta, T. P1 specificity of aqualysin I (a subtilisin-type serine protease) from Thermus aquaticus YT-1, using P1-substituted derivatives of Streptomyces subtilisin inhibitor. Biosci. Biotechnol. Biochem. 62 (1998) 2035–2038. [PMID: 9882104]
3.  Tanaka, T., Matsuzawa, H. and Ohta, T. Substrate specificity of aqualysin I, a bacterial thermophilic alkaline serine protease from Thermus aquaticus YT-1: Comparison with proteinase K, subtilisin BPN′ and subtilisin Carlsberg. Biosci. Biotechnol. Biochem. 62 (1998) 2161–2165. [PMID: 27393587]
[EC 3.4.21.111 created 2006]
 
 
EC 3.4.21.112     
Accepted name: site-1 protease
Reaction: Processes precursors containing basic and hydrophobic/aliphatic residues at P4 and P2, respectively, with a relatively relaxed acceptance of amino acids at P1 and P3
Other name(s): mammalian subtilisin/kexin isozyme 1; membrane-bound transcription factor site-1 protease; proprotein convertase SKI-1; proprotein convertase SKI-1/S1PPS1; S1P endopeptidase; S1P protease; site-1 peptidase; site-1 protease; SKI-1; SREBP proteinase; SREBP S1 protease; SREBP-1 proteinase; SREBP-2 proteinase; sterol regulatory element-binding protein proteinase; sterol regulatory element-binding protein site 1 protease; sterol-regulated luminal protease; subtilase SKI-1; subtilase SKI-1/S1P; subtilisin/kexin-isozyme 1
Comments: Cleaves sterol regulatory element-binding proteins (SREBPs) and thereby initiates a process by which the active fragments of the SREBPs translocate to the nucleus and activate genes controlling the synthesis and uptake of cholesterol and unsaturated fatty acids into the bloodstream [1]. The enzyme also processes pro-brain-derived neurotrophic factor and undergoes autocatalytic activation in the endoplasmic reticulum through sequential cleavages [5]. The enzyme can also process the unfolded protein response stress factor ATF6 at an Arg-His-Lys-Lys┼ site [4,8], and the envelope glycoprotein of the highly infectious Lassa virus [5,8] and Crimean Congo hemorrhagic fever virus at Arg-Arg-Lys-Lys┼ [7,8]. Belongs in peptidase family S8A.
References:
1.  Espenshade, P.J., Cheng, D., Goldstein, J.L. and Brown, M.S. Autocatalytic processing of site-1 protease removes propeptide and permits cleavage of sterol regulatory element-binding proteins. J. Biol. Chem. 274 (1999) 22795–22804. [PMID: 10428864]
2.  Cheng, D., Espenshade, P.J., Slaughter, C.A., Jaen, J.C., Brown, M.S. and Goldstein, J.L. Secreted site-1 protease cleaves peptides corresponding to luminal loop of sterol regulatory element-binding proteins. J. Biol. Chem. 274 (1999) 22805–22812. [PMID: 10428865]
3.  Touré, B.B., Munzer, J.S., Basak, A., Benjannet, S., Rochemont, J., Lazure, C., Chrétien, M. and Seidah, N.G. Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. J. Biol. Chem. 275 (2000) 2349–2358. [PMID: 10644685]
4.  Ye, J., Rawson, R.B., Komuro, R., Chen, X., Dave, U.P., Prywes, R., Brown, M.S. and Goldstein, J.L. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6 (2000) 1355–1364. [PMID: 11163209]
5.  Lenz, O., ter Meulen, J., Klenk, H.D., Seidah, N.G. and Garten, W. The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. Proc. Natl. Acad. Sci. USA 98 (2001) 12701–12705. [PMID: 11606739]
6.  Basak, A., Chrétien, M. and Seidah, N.G. A rapid fluorometric assay for the proteolytic activity of SKI-1/S1P based on the surface glycoprotein of the hemorrhagic fever Lassa virus. FEBS Lett. 514 (2002) 333–339. [PMID: 11943176]
7.  Vincent, M.J., Sanchez, A.J., Erickson, B.R., Basak, A., Chretien, M., Seidah, N.G. and Nichol, S.T. Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1. J. Virol. 77 (2003) 8640–8649. [PMID: 12885882]
8.  Seidah, N.G. and Chrétien, M. Proprotein convertase SKI-1/S1P. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, vol. 2, Elsevier, London, 2004, pp. 1845–1847.
[EC 3.4.21.112 created 2006]
 
 
EC 3.4.21.113     
Accepted name: pestivirus NS3 polyprotein peptidase
Reaction: Leu is conserved at position P1 for all four cleavage sites. Alanine is found at position P1′ of the NS4A-NS4B cleavage site, whereas serine is found at position P1′ of the NS3-NS4A, NS4B-NS5A and NS5A-NS5B cleavage sites
Other name(s): border disease virus NS3 endopeptidase; BDV NS3 endopeptidase; bovine viral diarrhea virus NS3 endopeptidase; BVDV NS3 endopeptidase; classical swine fever virus NS3 endopeptidase; CSFV NS3 endopeptidase; p80
Comments: The polyprotein of noncytopathogenic pestiviruses is cleaved co- and post-translationally into at least 11 proteins (Npro, C, Erns, E1, E2, p7, NS2-3, NS4A, NS4B, NS5A, and NS5B) [2]. The genomes of cytopathogenic pestivirus strains express at least one additional protein, called NS3 (p80) [2]. This enzyme, which resides in the N-terminal region of NS3 (nonstructural protein 3), is essential for generation of its own C-terminus and for processing of the downstream cleavage sites, leading to the release of the pestivirus nonstructural proteins NS4A, NS4B, NS5A and NS5B [1,2]. Belongs in peptidase family S31.
References:
1.  Wiskerchen, M. and Collett, M.S. Pestivirus gene expression: protein p80 of bovine viral diarrhea virus is a proteinase involved in polyprotein processing. Virology 184 (1991) 341–350. [PMID: 1651596]
2.  Tautz, N., Elbers, K., Stoll, D., Meyers, G. and Thiel, H.J. Serine protease of pestiviruses: determination of cleavage sites. J. Virol. 71 (1997) 5415–5422. [PMID: 9188613]
3.  Xu, J., Mendez, E., Caron, P.R., Lin, C., Murcko, M.A., Collett, M.S. and Rice, C.M. Bovine viral diarrhea virus NS3 serine proteinase: polyprotein cleavage sites, cofactor requirements, and molecular model of an enzyme essential for pestivirus replication. J. Virol. 71 (1997) 5312–5322. [PMID: 9188600]
4.  Tautz, N., Kaiser, A. and Thiel, H.J. NS3 serine protease of bovine viral diarrhea virus: characterization of active site residues, NS4A cofactor domain, and protease-cofactor interactions. Virology 273 (2000) 351–363. [PMID: 10915606]
[EC 3.4.21.113 created 2006]
 
 
EC 3.4.21.114     
Accepted name: equine arterivirus serine peptidase
Reaction: Cleavage of (Glu/Gln)┼(Gly/Ser/Ala) in arterivirus replicase translation products ORF1a and ORF1ab
Glossary: arterivirus nsp4; equine arteritis virus serine peptidase; 3C-like serine protease; 3C-like Ser protease; 3CLSP; nonstructural protein 4 serine protease, Nsp4 serine protease; nsp4 serine protease; Nsp4 SP; chymotrypsin-like serine proteinase nsp4
Comments: In the equine arterivirus (EAV), the replicase gene is translated into open reading frame 1a (ORF1a) and ORF1ab polyproteins. This enzyme is the main viral proteinase and processes five cleavage sites in the ORF1a protein and three in the ORF1b-encoded part of the ORF1ab protein to yield nonstructural proteins (nsp5-nsp12) [3]. It combines the catalytic system of a chymotrypsin-like serine peptidase (His-Asp-Ser catalytic triad) with the substrate specificity of a 3C-like serine peptidase (Glu or Gln) at the P1 position and a small amino-acid residue (Gly, Ser or Ala) at the P1′ position [1]. Cleavage of ORF1ab by this enzyme is essential for viral replication [2]. Belongs in peptidase family S32.
References:
1.  Snijder, E.J., Wassenaar, A.L., van Dinten, L.C., Spaan, W.J. and Gorbalenya, A.E. The arterivirus nsp4 protease is the prototype of a novel group of chymotrypsin-like enzymes, the 3C-like serine proteases. J. Biol. Chem. 271 (1996) 4864–4871. [PMID: 8617757]
2.  van Dinten, L.C., Rensen, S., Gorbalenya, A.E. and Snijder, E.J. Proteolytic processing of the open reading frame 1b-encoded part of arterivirus replicase is mediated by nsp4 serine protease and is essential for virus replication. J. Virol. 73 (1999) 2027–2037. [PMID: 9971783]
3.  Barrette-Ng, I.H., Ng, K.K., Mark, B.L., Van Aken, D., Cherney, M.M., Garen, C., Kolodenko, Y., Gorbalenya, A.E., Snijder, E.J. and James, M.N. Structure of arterivirus nsp4. The smallest chymotrypsin-like proteinase with an α/β C-terminal extension and alternate conformations of the oxyanion hole. J. Biol. Chem. 277 (2002) 39960–39966. [PMID: 12163505]
[EC 3.4.21.114 created 2006]
 
 
EC 3.4.21.115     
Accepted name: infectious pancreatic necrosis birnavirus Vp4 peptidase
Reaction: Cleaves the (Ser/Thr)-Xaa-Ala┼(Ser/Ala)-Gly motif in the polyprotein NH2-pVP2-VP4-VP3-COOH of infectious pancreatic necrosis virus at the pVP2-VP4 and VP4-VP3 junctions
Other name(s): infectious pancreatic necrosis virus protease; IPNV Vp4 protease; IPNV Vp4 peptidase; NS protease; NS-associated protease; Vp4 protease
Comments: Infectious pancreatic necrosis virus (IPNV) is a birnavirus that causes an acute, contagious disease in young salmonid fish [2]. As with most viruses that infect eukaryotic cells, the proteolytic processing of viral precursor proteins is a crucial step in the life cycle of this virus [2]. pVP2 is converted into VP2 by cleavage near the carboxy end of pVP2. This cleavage is most likely due to host-cell proteases rather than VP4 [2,3]. Differs from most serine peptidases in not having the catalytic triad Ser-His-Asp [2]. Belongs in peptidase family S50.
References:
1.  Manning, D.S. and Leong, J.C. Expression in Escherichia coli of the large genomic segment of infectious pancreatic necrosis virus. Virology 179 (1990) 16–25. [PMID: 2219718]
2.  Petit, S., Lejal, N., Huet, J.C. and Delmas, B. Active residues and viral substrate cleavage sites of the protease of the birnavirus infectious pancreatic necrosis virus. J. Virol. 74 (2000) 2057–2066. [PMID: 10666235]
3.  Dobos, P. The molecular biology of infectious pancreatic necrosis virus (IPNV). Annu. Rev. Fish Dis. 5 (1995) 25–54.
[EC 3.4.21.115 created 2006]
 
 
EC 3.4.21.116     
Accepted name: SpoIVB peptidase
Reaction: Self-cleaves Val52┼Asn53, Ala62┼Phe63 and Val74┼Thr75 at the N-terminus of SpoIVB
Other name(s): sporulation factor IV B protease
Comments: This enzyme plays a central role in a regulatory checkpoint (the σK checkpoint), which coordinates gene expression during the later stages of spore formation in Bacillus subtilis [1,3]. The enzyme activates proteolytic processing of a sporulation-specific sigma factor, pro-σK, to its mature and active form, σK, by self-cleavage [1,3]. The enzyme is also subject to secondary proteolysis, which presumably inactivates SpoIVB [3]. The enzyme is also essential for the formation of heat-resistant spores. Belongs in peptidase family S55.
References:
1.  Wakeley, P.R., Dorazi, R., Hoa, N.T., Bowyer, J.R. and Cutting, S.M. Proteolysis of SpolVB is a critical determinant in signalling of pro-σK processing in Bacillus subtilis. Mol. Microbiol. 36 (2000) 1336–1348. [PMID: 10931284]
2.  Hoa, N.T., Brannigan, J.A. and Cutting, S.M. The PDZ domain of the SpoIVB serine peptidase facilitates multiple functions. J. Bacteriol. 183 (2001) 4364–4373. [PMID: 11418578]
3.  Hoa, N.T., Brannigan, J.A. and Cutting, S.M. The Bacillus subtilis signaling protein SpoIVB defines a new family of serine peptidases. J. Bacteriol. 184 (2002) 191–199. [PMID: 11741860]
4.  Dong, T.C. and Cutting, S.M. SpoIVB-mediated cleavage of SpoIVFA could provide the intercellular signal to activate processing of pro-σK in Bacillus subtilis. Mol. Microbiol. 49 (2003) 1425–1434. [PMID: 12940997]
[EC 3.4.21.116 created 2006]
 
 
EC 3.4.21.117     
Accepted name: stratum corneum chymotryptic enzyme
Reaction: Cleavage of proteins with aromatic side chains in the P1 position
Other name(s): kallikrein 7; SCCE; KLK7; PRSS6; hK7
Comments: This enzyme has wide substrate specificity, being able to degrade heat-denatured bovine casein and the α-chain of native human fibrinogen. It cleaves the B chain of bovine insulin at Leu6┼Cya7, Tyr16┼Leu17, Phe25┼Tyr26 and Tyr26┼Thr27 [1]. It is thought to play a role in the desquamation (skin-shedding) of the outer layer of skin, the stratum corneum, by degrading intercellular cohesive structures [1,2]. Belongs in peptidase family S1A.
References:
1.  Skytt, A., Strömqvist, M. and Egelrud, T. Primary substrate specificity of recombinant human stratum corneum chymotryptic enzyme. Biochem. Biophys. Res. Commun. 211 (1995) 586–589. [PMID: 7794273]
2.  Egelrud, T. Purification and preliminary characterization of stratum corneum chymotryptic enzyme: a proteinase that may be involved in desquamation. J. Invest. Dermatol. 101 (1993) 200–204. [PMID: 8393902]
3.  Hansson, L., Strömqvist, M., Bäckman, A., Wallbrandt, P., Carlstein, A. and Egelrud, T. Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase. J. Biol. Chem. 269 (1994) 19420–19426. [PMID: 8034709]
4.  Yousef, G.M., Scorilas, A., Magklara, A., Soosaipillai, A. and Diamandis, E.P. The KLK7 (PRSS6) gene, encoding for the stratum corneum chymotryptic enzyme is a new member of the human kallikrein gene family - genomic characterization, mapping, tissue expression and hormonal regulation. Gene 254 (2000) 119–128. [PMID: 10974542]
5.  Vasilopoulos, Y., Cork, M.J., Murphy, R., Williams, H.C., Robinson, D.A., Duff, G.W., Ward, S.J. and Tazi-Ahnini, R. Genetic association between an AACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis. J. Invest. Dermatol. 123 (2004) 62–66. [PMID: 15191543]
[EC 3.4.21.117 created 2006]
 
 
EC 3.4.21.118     
Accepted name: kallikrein 8
Reaction: Cleavage of amide substrates following the basic amino acids Arg or Lys at the P1 position, with a preference for Arg over Lys
Other name(s): KLK8; PRSS19; human kallikrein 8; hK8; mK8; ovasin; tumor-associated differentially expressed gene 14; TADG-14; NP; neuropsin
Comments: The enzyme is activated by removal of an N-terminal prepropeptide [2,4]. The highest amidolytic activity is observed using Boc-Val-Pro-Arg┼7-amido-4-methylcoumarin, which is a substrate of α-thrombin [2,4]. Substrates lacking basic amino acids in the P1 position are not cleaved [4]. The enzyme degrades casein, fibronectin, gelatin, collagen type IV, fibrinogen, and high-molecular-mass kininogen [3] and is associated with diseases such as ovarian cancer and Alzheimer’s disease [4]. Belongs in peptidase family S1A.
References:
1.  Chen, Z.L., Yoshida, S., Kato, K., Momota, Y., Suzuki, J., Tanaka, T., Ito, J., Nishino, H., Aimoto, S., Kiyama, H. and Shiosaka, S. Expression and activity-dependent changes of a novel limbic-serine protease gene in the hippocampus. J. Neurosci. 15 (1995) 5088–5097. [PMID: 7623137]
2.  Shimizu, C., Yoshida, S., Shibata, M., Kato, K., Momota, Y., Matsumoto, K., Shiosaka, T., Midorikawa, R., Kamachi, T., Kawabe, A. and Shiosaka, S. Characterization of recombinant and brain neuropsin, a plasticity-related serine protease. J. Biol. Chem. 273 (1998) 11189–11196. [PMID: 9556608]
3.  Rajapakse, S., Ogiwara, K., Takano, N., Moriyama, A. and Takahashi, T. Biochemical characterization of human kallikrein 8 and its possible involvement in the degradation of extracellular matrix proteins. FEBS Lett. 579 (2005) 6879–6884. [PMID: 16337200]
4.  Kishi, T., Cloutier, S.M., Kündig, C., Deperthes, D. and Diamandis, E.P. Activation and enzymatic characterization of recombinant human kallikrein 8. Biol. Chem. 387 (2006) 723–731. [PMID: 16800733]
[EC 3.4.21.118 created 2006]
 
 
EC 3.4.21.119     
Accepted name: kallikrein 13
Reaction: Hydrolyses mouse Ren2 protein (a species of prorenin present in the submandibular gland) on the carboxy side of the arginine residue at the Lys-Arg┼ pair in the N-terminus, to yield mature renin
Other name(s): KLK13; kallikrein mK13; mGK-13; mK13; mKLK13; prorenin converting enzyme 1; PRECE-1; prorenin-converting enzyme; PRECE; proteinase P
Comments: The enzyme is specific for prorenin from the mouse submandibular gland, as prorenin from the mouse kidney (Ren1) and human prorenin are not substrates [1]. Site-directed mutagenesis studies have shown that the enzyme will also cleave prorenin when Lys-Arg is replaced by Arg-Arg or Gln-Arg but the rate of reaction is much slower when Lys-Lys is used. This enzyme is also able to process pro-interleukin-1β (pro-IL-1β) in mouse submandibular gland to form IL-1β [4]. Belongs in peptidase family S1A.
References:
1.  Nakayama, K., Kim, W.S., Nakagawa, T., Nagahama, M. and Murakami, K. Substrate specificity of prorenin converting enzyme of mouse submandibular gland. Analysis using site-directed mutagenesis. J. Biol. Chem. 265 (1990) 21027–21031. [PMID: 2250008]
2.  Kim, W.S., Hatsuzawa, K., Ishizuka, Y., Hashiba, K., Murakami, K. and Nakayama, K. A processing enzyme for prorenin in mouse submandibular gland. Purification and characterization. J. Biol. Chem. 265 (1990) 5930–5933. [PMID: 2180937]
3.  Kikkawa, Y., Yamanaka, N., Tada, J., Kanamori, N., Tsumura, K. and Hosoi, K. Prorenin processing and restricted endoproteolysis by mouse tissue kallikrein family enzymes (mK1, mK9, mK13, and mK22). Biochim. Biophys. Acta 1382 (1998) 55–64. [PMID: 9507064]
4.  Yao, C., Karabasil, M.R., Purwanti, N., Li, X., Akamatsu, T., Kanamori, N. and Hosoi, K. Tissue kallikrein mK13 is a candidate processing enzyme for the precursor of interleukin-1β in the submandibular gland of mice. J. Biol. Chem. 281 (2006) 7968–7976. [PMID: 16423834]
[EC 3.4.21.119 created 2006]
 
 
EC 3.4.21.120     
Accepted name: oviductin
Reaction: Preferential cleavage at Gly-Ser-Arg373┼ of glycoprotein gp43 in Xenopus laevis coelemic egg envelope to yield gp41
Other name(s): oviductal protease
Comments: The egg envelope of the South African clawed frog (Xenopus laevis) is modified during transit of the egg through the pars rectus oviduct, changing the egg envelope from an unfertilizable form to a fertilizable form. This process involves the conversion of glycoprotein gp43 to gp41 (ZPC) by the pars recta protease oviductin. It is thought that the enzymically active protease molecule comprises the N-terminal protease domain coupled to two C-terminal CUB domains, which are related to the mammalian spermadhesin molecules implicated in mediating sperm-envelope interactions [2]. The enzyme is also found in the Japanese toad (Bufo japonicus) [3]. Belongs in peptidase family S1.
References:
1.  Hardy, D.M. and Hedrick, J.L. Oviductin. Purification and properties of the oviductal protease that processes the molecular weight 43,000 glycoprotein of the Xenopus laevis egg envelope. Biochemistry 31 (1992) 4466–4472. [PMID: 1581303]
2.  Lindsay, L.L., Wieduwilt, M.J. and Hedrick, J.L. Oviductin, the Xenopus laevis oviductal protease that processes egg envelope glycoprotein gp43, increases sperm binding to envelopes, and is translated as part of an unusual mosaic protein composed of two protease and several CUB domains. Biol. Reprod. 60 (1999) 989–995. [PMID: 10084976]
3.  Hiyoshi, M., Takamune, K., Mita, K., Kubo, H., Sugimoto, Y. and Katagiri, C. Oviductin, the oviductal protease that mediates gamete interaction by affecting the vitelline coat in Bufo japonicus: its molecular cloning and analyses of expression and posttranslational activation. Dev. Biol. 243 (2002) 176–184. [PMID: 11846486]
[EC 3.4.21.120 created 2007]
 
 
EC 3.4.21.121     
Accepted name: Lys-Lys/Arg-Xaa endopeptidase
Reaction: Cleavage of -Lys-Lys┼ and -Lys-Arg┼ bonds.
Other name(s): ASP (Aeromonas sobria)-type peptidase; Aeromonas extracellular serine protease
Comments: The enzyme is a serine peptidase, which has been shown to cleave prothrombin and prekallikrein. It hydrolyses the complement component C5 releasing complement component C5a.
References:
1.  Kobayashi, H., Utsunomiya, H., Yamanaka, H., Sei, Y., Katunuma, N., Okamoto, K. and Tsuge, H. Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor. J. Biol. Chem. 284 (2009) 27655–27663. [PMID: 19654332]
2.  Nitta, H., Kobayashi, H., Irie, A., Baba, H., Okamoto, K. and Imamura, T. Activation of prothrombin by ASP, a serine protease released from Aeromonas sobria. FEBS Lett. 581 (2007) 5935–5939. [PMID: 18067862]
3.  Kobayashi, H., Takahashi, E., Oguma, K., Fujii, Y., Yamanaka, H., Negishi, T., Arimoto-Kobayashi, S., Tsuji, T. and Okamoto, K. Cleavage specificity of the serine protease of Aeromonas sobria, a member of the kexin family of subtilases. FEMS Microbiol. Lett. 256 (2006) 165–170. [PMID: 16487335]
4.  Imamura, T., Nitta, H., Wada, Y., Kobayashi, H. and Okamoto, K. Impaired plasma clottability induction through fibrinogen degradation by ASP, a serine protease released from Aeromonas sobria. FEMS Microbiol. Lett. 284 (2008) 35–42. [PMID: 18462393]
5.  Nitta, H., Imamura, T., Wada, Y., Irie, A., Kobayashi, H., Okamoto, K. and Baba, H. Production of C5a by ASP, a serine protease released from Aeromonas sobria. J. Immunol. 181 (2008) 3602–3608. [PMID: 18714034]
[EC 3.4.21.121 created 2013]
 
 
EC 3.4.22.1     
Accepted name: cathepsin B
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds. Preferentially cleaves -Arg-Arg┼ bonds in small molecule substrates (thus differing from cathepsin L). In addition to being an endopeptidase, shows peptidyl-dipeptidase activity, liberating C-terminal dipeptides
Other name(s): cathepsin B1 (obsolete); cathepsin II
Comments: An intracellular (lysosomal) enzyme in peptidase family C1 (papain family)
References:
1.  Bond, J.S. and Barrett, A.J. Degradation of fructose-1,6-bisphosphate aldolase by cathepsin B. A further example of peptidyldipeptidase activity of this proteinase. Biochem. J. 189 (1980) 17–25. [PMID: 7458901]
2.  Barrett, A.J. and Kirschke, H. Cathepsin B, cathepsin H and cathepsin L. Methods Enzymol. 80 (1981) 535–561. [PMID: 7043200]
3.  Polgár, L. and Csoma, C. Dissociation of ionizing groups in the binding cleft inversely controls the endo- and exopeptidase activities of cathepsin B. J. Biol. Chem. 262 (1987) 14448–14453. [PMID: 3312190]
4.  Barrett, A.J., Buttle, D.J. and Mason, R.W. Lysosomal cysteine proteinases. ISI Atlas of Science. Biochemistry 1 (1988) 256–260.
5.  Kirschke, H., Wikstrom, P. and Shaw, E. Active center differences between cathepsins L and B: the S1 binding region. FEBS Lett. 228 (1988) 128–130. [PMID: 3342870]
[EC 3.4.22.1 created 1972]
 
 
EC 3.4.22.2     
Accepted name: papain
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds, but preference for an amino acid bearing a large hydrophobic side chain at the P2 position. Does not accept Val in P1′
Other name(s): papayotin; summetrin; velardon; papaine; Papaya peptidase I
Comments: Type example of peptidase family C1 from latex of the papaya (Carica papaya) fruit. Inhibited by compound E-64 and proteins of the cystatin family.
References:
1.  Kamphuis, I.G., Drenth, J. and Baker, E.N. Thiol proteases. Comparative studies based on the high-resolution structures of papain and actinidin, and on amino acid sequence information for cathepsins B and H, and stem bromelain. J. Mol. Biol. 182 (1985) 317–329. [PMID: 3889350]
2.  Ménard, R. and Storer, A.C. Papain. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 555–557.
[EC 3.4.22.2 created 1961 as EC 3.4.4.10, transferred 1972 to EC 3.4.22.2, modified 1976, modified 2000]
 
 
EC 3.4.22.3     
Accepted name: ficain
Reaction: Similar to that of papain
Other name(s): ficin; debricin; higueroxyl delabarre
Comments: The major proteolytic component of the latex of fig, Ficus glabrata. Cysteine endopeptidases with similar properties are present in other members of the large genus Ficus. In peptidase family C1 (papain family).
References:
1.  Liener, I.E. and Friedenson, B. Ficin. Methods Enzymol. 19 (1970) 261–273.
2.  Brocklehurst, K., Willenbrock, F. and Salih, E. Cysteine proteinases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, Elsevier, Amsterdam, 1987, pp. 39–158.
[EC 3.4.22.3 created 1961 as EC 3.4.4.12, transferred 1972 to EC 3.4.22.3]
 
 
EC 3.4.22.4      
Transferred entry: bromelain (stem). Now EC 3.4.22.32 (stem bromelain) and EC 3.4.22.33 (fruit bromelain)
[EC 3.4.22.4 created 1972, deleted 1992 [EC 3.4.22.5 created 1972, incorporated 1978]]
 
 
EC 3.4.22.5      
Transferred entry: bromelain (juice). Now EC 3.4.22.32 (stem bromelain) and EC 3.4.22.33 (fruit bromelain)
[EC 3.4.22.5 created 1972, deleted 1978]
 
 
EC 3.4.22.6     
Accepted name: chymopapain
Reaction: Similar to that of papain
Other name(s): chymopapain A; chymopapain B; chymopapain S
Comments: The major endopeptidase of papaya (Carica papaya) latex. It has multiple chromatographic forms. In peptidase family C1 (papain family).
References:
1.  Brocklehurst, K., Willenbrock, F. and Salih, E. Cysteine proteinases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, Elsevier, Amsterdam, 1987, pp. 39–158.
2.  Jacquet, A., Kleinschmidt, T., Schnek, A.G., Looze, Y. and Braunitzer, G. The thiol proteinases from the latex of Carica papaya L. III. The primary structure of chymopapain. Biol. Chem. Hoppe-Seyler 370 (1989) 425–434. [PMID: 2500950]
3.  Buttle, D.J., Dando, P.M., Coe, P.F., Sharp, S.L., Shepherd, S.T. and Barrett, A.J. The preparation of fully active chymopapain free of contaminating proteinases. Biol. Chem. Hoppe-Seyler 371 (1990) 1083–1088. [PMID: 2085414]
[EC 3.4.22.6 created 1961 as EC 3.4.4.11, transferred 1972 to EC 3.4.22.6]
 
 
EC 3.4.22.7     
Accepted name: asclepain
Reaction: Similar to that of papain
Comments: From the latex of milkweed, Asclepias syriaca. It has multiple forms, and is in peptidase family C1 (papain family)
References:
1.  Brockbank, W.J. and Lynn, K.R. Purification and preliminary characterization of two asclepains from the latex of Asclepias syriaca L. (milkweed). Biochim. Biophys. Acta 578 (1979) 13–22. [PMID: 36921]
[EC 3.4.22.7 created 1972]
 
 
EC 3.4.22.8     
Accepted name: clostripain
Reaction: Preferential cleavage: Arg┼, including Arg┼Pro, but not Lys-
Other name(s): clostridiopeptidase B; clostridium histolyticum proteinase B; α-clostridipain; clostridiopeptidase
Comments: From the bacterium Clostridium histolyticum. It requires Ca2+ ions and is inhibited by EDTA. Type example of peptidase family C11.
References:
1.  Mitchell, W.M. Cleavage at arginine residues by clostripain. Methods Enzymol. 47 (1977) 165–170. [PMID: 927173]
2.  Gilles, A.-M., Imhoff, J.-M. and Keil, B. α-Clostripain. Chemical characterization, activity, and thiol content of the highly active form of clostripain. J. Biol. Chem. 254 (1979) 1462–1468. [PMID: 762145]
3.  Gilles, A.-M., Lecroisey, A. and Keil, B. Primary structure of α-clostripain light chain. Eur. J. Biochem. 145 (1984) 469–476. [PMID: 6391922]
[EC 3.4.22.8 created 1961 as EC 3.4.4.20, transferred 1972 to EC 3.4.22.8]
 
 
EC 3.4.22.9      
Transferred entry: yeast proteinase B. Now EC 3.4.21.48, cerevisin
[EC 3.4.22.9 created 1972, deleted 1981]
 
 
EC 3.4.22.10     
Accepted name: streptopain
Reaction: Preferential cleavage with hydrophobic residues at P2, P1 and P1′
Other name(s): Streptococcus peptidase A; streptococcal cysteine proteinase; Streptococcus protease
Comments: From the bacterium, group A Streptococcus. Formed from the proenzyme by limited proteolysis. Type example of peptidase family C10.
References:
1.  Elliott, S.D. and Liu, T.-Y. Streptococcal proteinase. Methods Enzymol. 19 (1970) 252–261.
2.  Liu, T.-Y. and Elliott, S.D. Streptococcal proteinase. In: Boyer, P.D. (Ed.), The Enzymes, 3rd edn, Academic Press, New York, 1971, pp. 609–647.
3.  Tai, J. Y., Kortt, A.A., Liu, T.-Y. and Elliott, S.D. Primary structure of streptococcal proteinase. III. Isolation of cyanogen bromide peptides: complete covalent structure of the polypeptide chain. J. Biol. Chem. 251 (1976) 1955–1959. [PMID: 1270417]
4.  Lo, S.-S., Fraser, B.A. and Liu, T.-Y. The mixed disulphide in the zymogen of streptococcal proteinase. Characterization and implication for its biosynthesis. J. Biol. Chem. 259 (1984) 11041–11045. [PMID: 6381494]
[EC 3.4.22.10 created 1961 as EC 3.4.4.18, transferred 1972 to EC 3.4.22.10]
 
 
EC 3.4.22.11      
Transferred entry: insulinase. Now EC 3.4.24.56, insulysin
[EC 3.4.22.11 created 1976, deleted 1978 [transferred to EC 3.4.99.45, deleted 1993]]
 
 
EC 3.4.22.12      
Transferred entry: γ-glutamyl hydrolase. Now EC 3.4.19.9, γ-glutamyl hydrolase
[EC 3.4.22.12 created 1978, deleted 1992]
 
 
EC 3.4.22.13      
Deleted entry:  staphylococcal cysteine proteinase
[EC 3.4.22.13 created 1978, modified 1981, deleted 1992]
 
 
EC 3.4.22.14     
Accepted name: actinidain
Reaction: Similar to that of papain
Other name(s): actinidin; Actinidia anionic protease; proteinase A2 of Actinidia chinensis
Comments: From the kiwi fruit or Chinese gooseberry (Actinidia chinensis). In peptidase family C1 (papain family)
References:
1.  Baker, E.N., Boland, M.J., Calder, P.C. and Hardman, M.J. The specificity of actinidin and its relationship to the structure of the enzyme. Biochim. Biophys. Acta 616 (1980) 30–34. [PMID: 7002215]
2.  Kamphuis, I.G., Drenth, J. and Baker, E.N. Thiol proteases. Comparative studies based on the high-resolution structures of papain and actinidin, and on amino acid sequence information for cathepsins B and H, and stem bromelain. J. Mol. Biol. 182 (1985) 317–329. [PMID: 3889350]
3.  Baker, E.N. and Drenth, J. The thiol proteases: stucture and mechanism. In: Jurnak, F.A. and McPherson, A. (Eds), Biological Macromolecules and Assemblies: Active Sites of Enzymes, vol. 3, John Wiley and Sons, New York, 1987, pp. 314–368.
[EC 3.4.22.14 created 1978]
 
 
EC 3.4.22.15     
Accepted name: cathepsin L
Reaction: Similar to that of papain. As compared to cathepsin B, cathepsin L exhibits higher activity towards protein substrates, but has little activity on Z-Arg-Arg-NHMec, and no peptidyl-dipeptidase activity
Other name(s): Aldrichina grahami cysteine proteinase
Comments: A lysosomal enzyme in peptidase family C1 (papain family) that is readily inhibited by the diazomethane inhibitor Z-Phe-Phe-CHN2 or the epoxide inhibitor E-64
References:
1.  Barrett, A.J. and Kirschke, H. Cathepsin B, cathepsin H and cathepsin L. Methods Enzymol. 80 (1981) 535–561. [PMID: 7043200]
2.  Barrett, A.J., Buttle, D.J. and Mason, R.W. Lysosomal cysteine proteinases. ISI Atlas of Science. Biochemistry 1 (1988) 256–260.
3.  Joseph, L.J., Chang, L.C., Stamenkovich, D. and Sukhatme, V.P. Complete nucleotide and deduced amino acid sequences of human and murine preprocathepsin L. An abundant transcript induced by transformation of fibroblasts. J. Clin. Invest. 81 (1988) 1621–1629. [PMID: 2835398]
4.  Kirschke, H., Wikstrom, P. and Shaw, E. Active center differences between cathepsins L and B: the S1 binding region. FEBS Lett. 228 (1988) 128–130. [PMID: 3342870]
[EC 3.4.22.15 created 1978 (EC 3.4.99.19 created 1972, incorporated 1981)]
 
 
EC 3.4.22.16     
Accepted name: cathepsin H
Reaction: Hydrolysis of proteins, acting as an aminopeptidase (notably, cleaving Arg┼ bonds) as well as an endopeptidase
Other name(s): cathepsin B3; benzoylarginine-naphthylamide (BANA) hydrolase (obsolete); cathepsin Ba, aleurain; N-benzoylarginine-β-naphthylamide hydrolase
Comments: Present in lysosomes of mammalian cells. In peptidase family C1 (papain family)
References:
1.  Barrett, A.J. and Kirschke, H. Cathepsin B, cathepsin H and cathepsin L. Methods Enzymol. 80 (1981) 535–561. [PMID: 7043200]
2.  Brömme, D., Bescherer, K., Kirschke, H. and Fittkau, S. Enzyme-substrate interactions in the hydrolysis of peptides by cathepsins B and H from rat liver. Biochem. J. 245 (1987) 381–385. [PMID: 3663163]
3.  Fuchs, R., Machleidt, W. and Gassen, H.G. Molecular cloning and sequencing of a cDNA coding for mature human kidney cathepsin H. Biol. Chem. Hoppe-Seyler 369 (1988) 469–475. [PMID: 2849458]
[EC 3.4.22.16 created 1981, modified 1989]
 
 
EC 3.4.22.17      
Transferred entry: calpain. Now EC 3.4.22.53, calpain-2
[EC 3.4.22.17 created 1981 [EC 3.4.24.5 created 1978, part incorporated 1989], deleted 2003]
 
 
EC 3.4.22.18      
Transferred entry: prolyl endopeptidase (thiol-dependent). Now EC 3.4.21.26, prolyl oligopeptidase
[EC 3.4.22.18 created 1981, deleted 1992]
 
 
EC 3.4.22.19      
Transferred entry: endo-oligopeptidase. Now EC 3.4.24.15, thimet oligopeptidase
[EC 3.4.22.19 created 1989, deleted 1992]
 
 
EC 3.4.22.20      
Deleted entry:  dinorphin-converting enzyme
[EC 3.4.22.20 created 1989, deleted 1992]
 
 
EC 3.4.22.21      
Transferred entry: yeast cysteine proteinase E. Now EC 3.4.25.1, proteasome endopeptidase complex
[EC 3.4.22.21 created 1989, deleted 1992]
 
 
EC 3.4.22.22      
Transferred entry: yeast cysteine proteinase D. Now EC 3.4.24.37, saccharolysin
[EC 3.4.22.22 created 1989, deleted 1992]
 
 
EC 3.4.22.23      
Transferred entry: yeast cysteine proteinase F. Now EC 3.4.21.61, kexin
[EC 3.4.22.23 created 1989, deleted 1992]
 
 
EC 3.4.22.24     
Accepted name: cathepsin T
Reaction: Interconversion of the three forms of tyrosine aminotransferase, EC 2.6.1.5
Comments: Degrades azocasein and denatured hemoglobin; the only native protein on which it has been shown to act is tyrosine aminotransferase
References:
1.  Gohda, E. and Pitot, H.C. Purification and characterization of a new thiol proteinase from rat kidney. Biochim. Biophys. Acta 659 (1981) 114–122. [PMID: 7248311]
2.  Gohda, E. and Pitot, H.C. A new thiol proteinase from rat liver. J. Biol. Chem. 256 (1981) 2567–2572. [PMID: 6780567]
3.  Pitot, H.C. and Gohda, E. Cathepsin T. Methods Enzymol. 142 (1987) 279–289. [PMID: 2885716]
[EC 3.4.22.24 created 1990]
 
 
EC 3.4.22.25     
Accepted name: glycyl endopeptidase
Reaction: Preferential cleavage: Gly┼, in proteins and small molecule substrates
Other name(s): papaya peptidase B; papaya proteinase IV; glycine-specific proteinase; chymopapain; Papaya proteinase 4; PPIV; chymopapain M
Comments: From the papaya plant, Carica papaya. Not inhibited by chicken cystatin, unlike most other homologues of papain, but in peptidase family C1 (papain family)
References:
1.  Polgár, L. Isolation of highly active papaya peptidases A and B from commercial chymopapain. Biochim. Biophys. Acta 658 (1981) 262–269. [PMID: 7018581]
2.  Buttle, D.J., Kembhavi, A.A., Sharp, S.L., Shute, R.E., Rich, D.H. and Barrett, A.J. Affinity purification of the novel cysteine proteinase papaya proteinase IV and papain from papaya latex. Biochem. J. 261 (1989) 469–476. [PMID: 2505761]
3.  Ritonja, A., Buttle, D.J., Rawlings, N.D., Turk, V. and Barrett, A.J. Papaya proteinase IV amino acid sequence. FEBS Lett. 258 (1989) 109–112. [PMID: 2591528]
4.  Buttle, D.J., Ritonja, A., Pearl, L.H., Turk, V. and Barrett, A.J. Selective cleavage of glycyl bonds by papaya proteinase IV. FEBS Lett. 260 (1990) 195–197. [PMID: 2404797]
5.  Buttle, D.J., Ritonja, A., Dando, P.M., Abrahamson, M., Shaw, E.N., Wikstrom, P., Turk, V. and Barrett, A.J. Interaction of papaya proteinase IV with inhibitors. FEBS Lett. 262 (1990) 58–60. [PMID: 1690669]
[EC 3.4.22.25 created 1992]
 
 
EC 3.4.22.26     
Accepted name: cancer procoagulant
Reaction: Specific cleavage of Arg┼Ile bond in Factor X to form Factor Xa
Comments: Apparently produced only by malignant and fetal cells
References:
1.  Falanga, A. and Gordon, S.G. Isolation and characterization of cancer procoagulant: a cysteine proteinase from malignant tissue. Biochemistry 24 (1985) 5558–5567. [PMID: 3935163]
2.  Falanga, A., Shaw, E., Donati, M.B., Consonni, R., Barbui, T. and Gordon, S. Inhibition of cancer procoagulant by peptidyl diazomethyl ketones and peptidyl sulfonium salts. Thromb. Res. 54 (1989) 389–398. [PMID: 2772865]
[EC 3.4.22.26 created 1992]
 
 
EC 3.4.22.27     
Accepted name: cathepsin S
Reaction: Similar to cathepsin L, but with much less activity on Z-Phe-Arg┼NHMec, and more activity on the Z-Val-Val-Arg┼ compound
Comments: A lysosomal cysteine endopeptidase that is unusual amongst such enzymes for its stability to neutral pH. In peptidase family C1 (papain family)
References:
1.  Turnšek, T., Kregar, I. and Lebez, D. Acid sulphydryl protease from calf lymph nodes. Biochim. Biophys. Acta 403 (1975) 514–520. [PMID: 1182153]
2.  Brömme, D., Steinert, A., Friebe, S., Fittkau, S., Wiederanders, B. and Kirschke, H. The specificity of bovine spleen cathepsin S. A comparison with rat liver cathepsins L and B. Biochem. J. 264 (1989) 475–485. [PMID: 2604727]
3.  Kirschke, H., Wiederanders, B., Brömme, D. and Rinne, A. Cathepsin S from bovine spleen. Purification, distribution, intracellular localization and action on proteins. Biochem. J. 264 (1989) 467–473. [PMID: 2690828]
[EC 3.4.22.27 created 1992]
 
 
EC 3.4.22.28     
Accepted name: picornain 3C
Reaction: Selective cleavage of Gln┼Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly
Other name(s): picornavirus endopeptidase 3C; poliovirus protease 3C; rhinovirus protease 3C; foot-and-mouth protease 3C; poliovirus proteinase 3C; rhinovirus proteinase 3C; coxsackievirus 3C proteinase; foot-and-mouth-disease virus proteinase 3C; 3C protease; 3C proteinase; cysteine proteinase 3C; hepatitis A virus 3C proteinase; protease 3C; tomato ringspot nepovirus 3C-related protease
Comments: From entero-, rhino-, aphto- and cardioviruses. Larger than the homologous virus picornain 2A. Type example of peptidase family C3
References:
1.  Ivanoff, L.A., Towatari, T., Ray, J., Korant, B.D. and Petteway, S.R. Expression and site-specific mutagenesis of the poliovirus 3C protease in Escherichia coli. Proc. Natl Acad. Sci. USA 83 (1986) 5392–5396. [PMID: 3016701]
2.  Bazan, J.F. and Fletterick, R.J. Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications. Proc. Natl Acad. Sci. USA 85 (1988) 7872–7876. [PMID: 3186696]
3.  Kräusslich, H.-G. and Wimmer, E. Viral proteinases. Annu. Rev. Biochem. 57 (1988) 701–754. [PMID: 3052288]
4.  Nicklin, M.J.H., Harris, K.S., Pallai, P.V. and Wimmer, E. Poliovirus proteinase 3C: large-scale expression, purification, and specific cleavage activity on natural and synthetic substrates in vitro. J. Virol. 62 (1988) 4586–4593. [PMID: 2846872]
[EC 3.4.22.28 created 1992]
 
 
EC 3.4.22.29     
Accepted name: picornain 2A
Reaction: Selective cleavage of Tyr┼Gly bond in picornavirus polyprotein
Other name(s): picornavirus endopeptidase 2A; poliovirus protease 2A; rhinovirus protease 2A; 2A protease; 2A proteinase; protease 2A; proteinase 2Apro; picornaviral 2A proteinase; Y-G proteinase 2A; poliovirus proteinase 2A; poliovirus protease 2Apro; picornaviral 2A proteinase
Comments: From entero-, rhino-, aphto- and cardioviruses. Smaller than the homologous picornain 3C, which is also in peptidase family C3 (picornain 3C family)
References:
1.  Bazan, J.F. and Fletterick, R.J. Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications. Proc. Natl Acad. Sci. USA 85 (1988) 7872–7876. [PMID: 3186696]
2.  König, H. and Rosenwirth, B. Purification and partial characterization of poliovirus protease 2A by means of a functional assay. J. Virol. 62 (1988) 1243–1250. [PMID: 2831385]
3.  Kräusslich, H.-G. and Wimmer, E. Viral proteinases. Annu. Rev. Biochem. 57 (1988) 701–754. [PMID: 3052288]
[EC 3.4.22.29 created 1992]
 
 
EC 3.4.22.30     
Accepted name: caricain
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds, similar to those of papain and chymopapain
Other name(s): papaya peptidase A; papaya peptidase II; papaya proteinase ; papaya proteinase III; papaya proteinase 3; proteinase ω; papaya proteinase A; chymopapain S; Pp
Comments: From papaya plant, Carica papaya. In peptidase family C1 (papain family)
References:
1.  Schack, P. Fractionation of proteolytic enzymes of dried papaya latex. Isolation and preliminary characterization of a new proteolytic enzyme. C. R. Trav. Carlesberg 36 (1967) 67–83. [PMID: 6043136]
2.  Robinson, G.W. Isolation and characterization of papaya peptidase A from commercial chymopapain. Biochemistry 16 (1975) 3695–3700. [PMID: 240390]
3.  Polgár, L. Problems of classification of papaya latex proteinases. Biochem. J. 221 (1984) 555–556. [PMID: 6383350]
4.  Brocklehurst, K., Salih, E., McKee, R. and Smith, H. Fresh non-fruit latex of Carica papaya contains papain, multiple forms of chymopapain A and papaya proteinase . Biochem. J. 228 (1985) 525–527. [PMID: 4015629]
5.  Zucker, S., Buttle, D.J., Nicklin, M.J.H. and Barrett, A.J. Proteolytic activities of papain, chymopapain and papaya proteinase III. Biochim. Biophys. Acta 828 (1985) 196–204. [PMID: 3919769]
6.  Dubois, T., Kleinschmidt, T., Schnek, A.G., Looze, Y. and Braunitzer, G. The thiol proteinases from the latex of Carica papaya L. II. The primary structure of proteinase . Biol. Chem. Hoppe-Seyler 369 (1988) 741–754. [PMID: 3063283]
[EC 3.4.22.30 created 1992]
 
 
EC 3.4.22.31     
Accepted name: ananain
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds. Best reported small molecule substrate Bz-Phe-Val-Arg┼NHMec, but broader specificity than fruit bromelain
Other name(s): stem bromelain; fruit bromelain
Comments: From stem of pineapple plant, Ananas comosus. Differs from stem and fruit bromelains in being inhibited by chicken cystatin. In peptidase family C1 (papain family)
References:
1.  Rowan, A.D., Buttle, D.J. and Barrett, A.J. Ananain: a novel cysteine proteinase found in pineapple stem. Arch. Biochem. Biophys. 267 (1988) 262–270. [PMID: 3196029]
2.  Rowan, A.D., Buttle, D.J. and Barrett, A.J. The cysteine proteinases of the pineapple plant. Biochem. J. 266 (1990) 869–875. [PMID: 2327970]
[EC 3.4.22.31 created 1992]
 
 
EC 3.4.22.32     
Accepted name: stem bromelain
Reaction: Broad specificity for cleavage of proteins, but strong preference for Z-Arg-Arg┼NHMec amongst small molecule substrates
Other name(s): bromelain; pineapple stem bromelain
Comments: The most abundant of the cysteine endopeptidases of the stem of the pineapple plant, Ananas comosus. Distinct from the bromelain found in the pineapple fruit (EC 3.4.22.33). Scarcely inhibited by chicken cystatin and also very slowly inactivated by E-64. In peptidase family C1 (papain family).
References:
1.  Brocklehurst, K., Willenbrock, F. and Salih, E. Cysteine proteinases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, Elsevier, Amsterdam, 1987, pp. 39–158.
2.  Rowan, A.D., Buttle, D.J. and Barrett, A.J. Ananain: a novel cysteine proteinase found in pineapple stem. Arch. Biochem. Biophys. 267 (1988) 262–270. [PMID: 3196029]
3.  Ritonja, A., Rowan, A.B., Buttle, D.J., Rawlings, N.D., Turk, V. and Barrett, A.J. Stem bromelain: amino acid sequence and implications for weak binding to cystatin. FEBS Lett. 247 (1989) 419–429. [PMID: 2714443]
4.  Rowan, A.D., Buttle, D.J. and Barrett, A.J. The cysteine proteinases of the pineapple plant. Biochem. J. 266 (1990) 869–875. [PMID: 2327970]
[EC 3.4.22.32 created 1965 as EC 3.4.4.24, transferred 1972 to EC 3.4.22.4, part transferred 1992 to EC 3.4.22.32]
 
 
EC 3.4.22.33     
Accepted name: fruit bromelain
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds. Bz-Phe-Val-Arg┼NHMec is a good synthetic substrate, but there is no action on Z-Arg-Arg-NHMec (c.f. stem bromelain)
Other name(s): juice bromelain; ananase; bromelase; bromelin; extranase; juice bromelain; pinase; pineapple enzyme; traumanase; fruit bromelain FA2
Comments: From the pineapple plant, Ananas comosus. Scarcely inhibited by chicken cystatin. Another cysteine endopeptidase, with similar action on small molecule substrates, pinguinain, is obtained from the related plant, Bromelia pinguin, but pinguinain differs from fruit bromelain in being inhibited by chicken cystatin [4].
References:
1.  Sasaki, M., Kato, T. and Iida, S. Antigenic determinant common to four kinds of thiol proteases of plant origin. J. Biochem. (Tokyo) 74 (1973) 635–637. [PMID: 4127920]
2.  Yamada, F., Takahashi, N. and Murachi, T. Purification and characterization of a proteinase from pineapple fruit, fruit bromelain FA2. J. Biochem. (Tokyo) 79 (1976) 1223–1234. [PMID: 956152]
3.  Ota, S., Muta, E., Katanita, Y. and Okamoto, Y. Reinvestigation of fractionation and some properties of the proteolytically active components of stem and fruit bromelains. J. Biochem. (Tokyo) 98 (1985) 219–228. [PMID: 4044551]
4.  Rowan, A.D., Buttle, D.J. and Barrett, A.J. The cysteine proteinases of the pineapple plant. Biochem. J. 266 (1990) 869–875. [PMID: 2327970]
[EC 3.4.22.33 created 1965 as EC 3.4.4.24, transferred 1972 to EC 3.4.22.4, part transferred 1992 to EC 3.4.22.33]
 
 
EC 3.4.22.34     
Accepted name: legumain
Reaction: Hydrolysis of proteins and small molecule substrates at -Asn┼Xaa- bonds
Other name(s): asparaginyl endopeptidase; citvac; proteinase B (ambiguous); hemoglobinase (ambiguous); PRSC1 gene product (Homo sapiens); vicilin peptidohydrolase; bean endopeptidase; vicilin peptidohydrolase
Comments: Best known from legume seeds, the trematode Schistosoma mansoni and mammalian lysosomes. Not inhibited by compound E-64. Type example of peptidase family C13
References:
1.  Hara-Nishimura, I. Asparaginyl endopeptidase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 746–749.
2.  Dalton, J.P. and Brindley, P.J. Schistosome legumain. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 749–754.
3.  Chen, J.-M., Rawlings, N.D., Stevens, R.A.E. and Barrett, A.J. Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases. FEBS Lett. 441 (1998) 361–365. [PMID: 9891971]
[EC 3.4.22.34 created 1992, modified 2000]
 
 
EC 3.4.22.35     
Accepted name: histolysain
Reaction: Hydrolysis of proteins, including basement membrane collagen and azocasein. Preferential cleavage: Arg-Arg┼ in small molecule substrates including Z-Arg-Arg┼NHMec
Other name(s): histolysin; histolysin; Entamoeba histolytica cysteine proteinase; amebapain; Entamoeba histolytica cysteine protease; Entamoeba histolytica neutral thiol proteinase
Comments: From the protozoan, Entamoeba histolytica. In peptidase family C1 (papain family)
References:
1.  Lushbaugh, W.B., Hofbauer, A.F. and Pittman, F.E. Entamoeba histolytica: purification of cathepsin B. Exp. Parasitol. 59 (1985) 328–336. [PMID: 2860002]
2.  Luaces, A.L. and Barrett, A.J. Affinity purification and biochemical characterization of histolysin: the major cysteine proteinase of Entamoeba histolytica. Biochem. J. 250 (1988) 903–909. [PMID: 2898937]
[EC 3.4.22.35 created 1992]
 
 
EC 3.4.22.36     
Accepted name: caspase-1
Reaction: Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Tyr-Val-Ala-Asp┼
Other name(s): interleukin 1β-converting enzyme; protease VII; protease A; interleukin 1β precursor proteinase; interleukin 1 converting enzyme; interleukin 1β-converting endopeptidase; interleukin-1β convertase; interleukin-1β converting enzyme; interleukin-1β precursor proteinase; prointerleukin 1β protease; precursor interleukin-1β converting enzyme; pro-interleukin 1β proteinase; ICE
Comments: From mammalian monocytes. This enzyme is part of the family of inflammatory caspases, which also includes caspase-4 (EC 3.4.22.57) and caspase-5 (EC 3.4.22.58) in humans and caspase-11 (EC 3.4.22.64), caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [6,7]. Cleaves pro-interleukin-1β (pro-IL-1β) to form mature IL-1β, a potent mediator of inflammation. Also activates the proinflammatory cytokine, IL-18, which is also known as interferon-γ-inducing factor [6]. Inhibited by Ac-Tyr-Val-Ala-Asp-CHO. Caspase-11 plays a critical role in the activation of caspase-1 in mice, whereas caspase-4 enhances its activation in humans [7]. Belongs in peptidase family C14.
References:
1.  Howard, A., Kostura, M.J., Thornberry, N., Ding, G.J.., Limjuco, G., Weidner, J., Salley, J.P., Hogquist, K.A., Chaplin, D.D., Mumford, R.A., Schmidt, J.A. and Tocci, M.J. IL-1 converting enzyme requires aspartic acid residues for processing of the IL-1β precursor at two distinct sites and does not cleave 31-kDa IL-1α. J. Immunol. 147 (1991) 2964–2969. [PMID: 1919001]
2.  Thornberry, N.A., Bull, H.G., Calaycay, J.R., Chapman, K.T., Howard, A.D., Kostura, M.J., Miller, D.K., Molineaux, S.M., Weidner, J.R., Aunins, J., Elliston, K.O., Ayala, J.M., Casano, F J., Chin, J., Ding, G.J.-F., Egger, L.A., Gaffney, E.P., Limjuco, G., Palyha, O.C., Raju, S.M., Rolando, A.M., Salley, J.P., Yamin, T.-T. and Tocci, M.J. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356 (1992) 768–774. [PMID: 1574116]
3.  Thornberry, N.A. Interleukin-1β converting enzyme. Methods Enzymol. 244 (1994) 615–631. [PMID: 7845238]
4.  Alnemri, E.S., Livingston, D.J., Nicholson, D.W., Salvesen, G., Thornberry, N.A., Wong, W.W. and Yuan, J.Y. Human ICE/CED-3 protease nomenclature. Cell 87 (1996) 171. [PMID: 8861900]
5.  Margolin, N., Raybuck, S.A., Wilson, K.P., Chen, W.Y., Fox, T., Gu, Y. and Livingston, D.J. Substrate and inhibitor specificity of interleukin-1β-converting enzyme and related caspases. J. Biol. Chem. 272 (1997) 7223–7228. [PMID: 9054418]
6.  Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561–574. [PMID: 15163405]
7.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.36 created 1993, modified 1997, modified 2007]
 
 
EC 3.4.22.37     
Accepted name: gingipain R
Reaction: Hydrolysis of proteins and small molecule substrates, with a preference for Arg in P1
Other name(s): Arg-gingipain; gingipain-1; argingipain; Arg-gingivain-55 proteinase; Arg-gingivain-70 proteinase; Arg-gingivain-75 proteinase; arginine-specific cysteine protease; arginine-specific gingipain; arginine-specific gingivain; RGP-1; RGP
Comments: A secreted endopeptidase from the bacterium Porphyromonas gingivalis. Strongly activated by glycine [1], and stabilized by Ca2+. Precursor molecule contains a hemagglutinin domain [2,3]. Misleadingly described in some literature as "trypsin-like", being a cysteine peptidase, type example of family C25
References:
1.  Chen, Z., Potempa, J., Polanowski, A., Wikstrom, M. and Travis, J. Purification and characterization of a 50-kDa cysteine proteinase (gingipain) from Porphyromonas gingivalis. J. Biol. Chem. 267 (1992) 18896–18901. [PMID: 1527017]
2.  Kirszbaum, L., Sotiropoulos, C., Jackson, C., Cleal, S., Slakeski, N. and Reynolds, E.C. Complete nucleotide sequence of a gene prtR of Porphyromonas gingivalis W50 encoding a 132 kDa protein that contains an arginine-specific thiol endopeptidase domain and a haemagglutinin domain. Biochem. Biophys. Res. Commun. 207 (1995) 424–431. [PMID: 7857299]
3.  Pavloff, N., Potempa, J., Pike, R.N., Prochazka, V., Kiefer, M.C., Travis, J. and Barr, P.J. Molecular cloning and structural characterization of the Arg-gingipain proteinase of Porphyromonas gingivalis. Biosynthesis as a proteinase-adhesin polyprotein. J. Biol. Chem. 270 (1995) 1007–1010. [PMID: 7836351]
[EC 3.4.22.37 created 1996]
 
 
EC 3.4.22.38     
Accepted name: cathepsin K
Reaction: Broad proteolytic activity. With small-molecule substrates and inhibitors, the major determinant of specificity is P2, which is preferably Leu, Met > Phe, and not Arg
Other name(s): cathepsin O and cathepsin X (both misleading, having been used for other enzymes); cathepsin O2
Comments: Prominently expressed in mammalian osteoclasts, and believed to play a role in bone resorption. In peptidase family C1 (papain family)
References:
1.  Inaoka, T., Bilbe, G., Ishibashi, O., Tezuka, K., Kumegawa, M. and Kokubo, T. Molecular cloning of human cDNA for cathepsin K: Novel cysteine proteinase predominantly expressed in bone. Biochem. Biophys. Res. Commun. 206 (1995) 89–96. [PMID: 7818555]
2.  Bossard, M.J., Tomaszek, T.A., Thompson, S.K., Amegadzie, B.Y., Hanning, C.R., Jones, C., Kurdyla, J.T., McNulty, D.E., Drake, F.H., Gowen, M. and Levy, M.A. Proteolytic activity of human osteoclast cathepsin K - Expression, purification, activation, and substrate identification. J. Biol. Chem. 271 (1996) 12517–12524. [PMID: 8647860]
3.  Bromme, D., Klaus, J.L., Okamoto, K., Rasnick, D. and Palmer, J.T. Peptidyl vinyl sulphones: A new class of potent and selective cysteine protease inhibitors - S2P2 specificity of human cathepsin O2 in comparison with cathepsins S and L. Biochem. J. 315 (1996) 85–89. [PMID: 8670136]
4.  Zhao, B.G., Janson, C.A., Amegadzie, B.Y., D'Alessio, K., Griffin, C., Hanning, C.R., Jones, C., Kurdyla, J., McQueney, M., Qiu, X.Y., Smith, W.W. and Abdel-Meguid, S.S. Crystal structure of human osteoclast cathepsin K complex with E-64. Nature Struct. Biol. 4 (1997) 109–111. [PMID: 9033588]
5.  McGrath, M.E., Klaus, J.L., Barnes, M.G. and Brömme, D. Crystal structure of human cathepsin K complexed with a potent inhibitor. Nature Struct. Biol. 4 (1997) 105–109. [PMID: 9033587]
[EC 3.4.22.38 created 1997]
 
 
EC 3.4.22.39     
Accepted name: adenain
Reaction: Cleaves proteins of the adenovirus and its host cell at two consensus sites: -Yaa-Xaa-Gly-Gly┼Xaa- and -Yaa-Xaa-Gly-Xaa┼Gly- (in which Yaa is Met, Ile or Leu, and Xaa is any amino acid)
Comments: A cysteine endopeptidase from adenoviruses, the type example of peptidase family C5, with a protein fold unlike that known for any other peptidase [2]. Activity is greatly stimulated by the binding to the enzyme of an 11-residue peptide from the adenovirus capsid protein pre-VI at a site separate from the active site [1]
References:
1.  Webster, A., Hay, R.T. and Kemp, G. The adenovirus protease is activated by a virus-coded disulphide-linked peptide. Cell 72 (1993) 274–275. [PMID: 8422686]
2.  Ding, J.Z., McGrath, W.J., Sweet, R.M. and Mangel, W.F. Crystal structure of the human adenovirus proteinase with its 11 residue cofactor. EMBO J. 15 (1996) 1778–1783. [PMID: 8617222]
3.  Weber, J.M. Adenovirus protease. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 741–743.
[EC 3.4.22.39 created 2000]
 
 
EC 3.4.22.40     
Accepted name: bleomycin hydrolase
Reaction: Inactivates bleomycin B2 (a cytotoxic glycometallopeptide) by hydrolysis of a carboxyamide bond of β-aminoalanine, but also shows general aminopeptidase activity. The specificity varies somewhat with source, but amino acid arylamides of Met, Leu and Ala are preferred [1]
Other name(s): aminopeptidase C (Lactococcus lactis) [4]
Comments: The molecule is a homohexamer in which the monomers have a papain-like tertiary structure (in peptidase family C1). The active sites are on the walls of a central channel through the molecule, and access of substrate molecules to them is obstructed by this and by the C-terminus of each polypeptide chain [3]. Bleomycin can scarcely be the natural substrate, and there are reports of limited endopeptidase activity. Known from bacteria as well as eukaryotic organisms. Hydrolase H from chicken muscle has many similarities to bleomycin hydrolase, but hydrolyses Ph-CO-Arg-2-naphthylamine as well as aminopeptidase substrates [2].
References:
1.  Brömme, D., Rossi, A.B., Smeekens, S.P., Anderson, D.C. & Payan, D.G. Human bleomycin hydrolase: molecular cloning, sequencing, functional expression, and enzymatic characterization. Biochemistry 35 (1996) 6706–6714. [PMID: 8639621]
2.  Adachi, H., Tsujimoto, M., Fukasawa, M., Sato, Y., Arai, H., Inoue, K. and Nishimura, T. cDNA cloning and expression of chicken aminopeptidase H, possessing endopeptidase as well as aminopeptidase activity. Eur. J. Biochem. 245 (1997) 283–288. [PMID: 9151954]
3.  Zheng, W., Johnston, S.A. & Joshua-Tor, L. The unusual active site of Gal6/bleomycin hydrolase can act as a carboxypeptidase, aminopeptidase, and peptide ligase. Cell 93 (1998) 103–109. [PMID: 9546396]
4.  Mistou, M.Y. & Gripon, J.C. Catalytic properties of the cysteine aminopeptidase PepC, a bacterial bleomycin hydrolase. Biochim. Biophys. Acta 1383 (1998) 63–70. [PMID: 9546047]
[EC 3.4.22.40 created 2000]
 
 
EC 3.4.22.41     
Accepted name: cathepsin F
Reaction: The recombinant enzyme cleaves synthetic substrates with Phe and Leu (better than Val) in P2, with high specificity constant (kcat/Km) comparable to that of cathepsin L
Comments: Cathepsin F is a lysosomal cysteine endopeptidase of family C1 (papain family), most active at pH 5.9. The enzyme is unstable at neutral pH values and is inhibited by compound E-64. Cathepsin F is expressed in most tissues of human, mouse and rat. Human gene locus: 11q13.1-13.3
References:
1.  Santamaría, I., Velasco, G., Pendás, A.M., Paz, A. and López-Otín, C. Molecular cloning and structural and functional chararcterization of cathepsin F, a new cysteine proteinase of the papain family with a long propeptide domain. J. Biol. Chem. 274 (1999) 13800–13809. [PMID: 10318784]
2.  Nägler, D.K. Sulea, T. and Ménard, R. Full length cDNA of human cathepsin F predicts the presence of a cystatin domain at the N-terminus of the cysteine protease zymogen. Biochem. Biophys. Res. Commun. 257 (1999) 313–318. [PMID: 10198209]
3.  Wex, T., Levy, B., Wex, H. and Brömme, D. Human cathepsins F and W: A new subgroup of cathepsins. Biochem. Biophys. Res. Commun. 259 (1999) 401–407. [PMID: 10362521]
4.  Wang, B., Shi, G.-P., Yao, P.M., Li, Z., Chapman, H.A. and Brömme, D. Human cathepsin F. Molecular cloning, functional expression, tissue localization, and enzymatic characterization. J. Biol. Chem. 273 (1998) 32000–32008. [PMID: 9822672]
[EC 3.4.22.41 created 2000]
 
 
EC 3.4.22.42     
Accepted name: cathepsin O
Reaction: The recombinant human enzyme hydrolyses synthetic endopeptidase substrates including Z-Phe-Arg-NHMec and Z-Arg-Arg-NHMec
Comments: Cathepsin O is a lysosomal cysteine peptidase of family C1 (papain family). The recombinant human enzyme is catalytically active at pH 6.0 and is inhibited by compound E-64. Cathepsin O is ubiquitously expressed in human tissues and the human gene locus is 4q31-32
References:
1.  Santamaría, I., Pendás, A.M. and López-Otín, C. Genomic structure and chromosomal localization of a human cathepsin O gene (CTSO). Genomics 53 (1998) 231–234. [PMID: 9790772]
2.  Velasco, G., Ferrando, A.A., Puente, X.S., Sanchez, L.M. and López-Otín, C. Human cathepsin O. Molecular cloning from a breast carcinoma, production of the active enzyme in Escherichia coli, and expression analysis in human tissues. J. Biol. Chem. 269 (1994) 27136–27142. [PMID: 7929457]
[EC 3.4.22.42 created 2000]
 
 
EC 3.4.22.43     
Accepted name: cathepsin V
Reaction: The recombinant enzyme hydrolyses proteins (serum albumin, collagen) and synthetic substrates (Z-Phe-Arg-NHMec > Z-Leu-Arg-NHMec > Z-Val-Arg-NHMec)
Other name(s): Cathepsin L2; cathepsin U
Comments: Cathepsin V is a human lysosomal cysteine endopeptidase of family C1 (papain family) that is maximally active at pH 5.7 and unstable at neutral pH. Compound E-64, leupeptin and chicken cystatin are inhibitors. Human cathepsin V shows expression restricted to thymus, testis, corneal epithelium and some colon and breast carcinomas. Human gene locus: 9q22.2
References:
1.  Brömme, D., Li, Z., Barnes, M. and Mehler, E. Human cathepsin V functional expression, tissue distribution, electrostatic surface potential, enzymatic characterization, and chromosomal localization. Biochemistry 38 (1999) 2377–2385. [PMID: 10029531]
2.  Adachi, W., Kawamoto, S., Ohno, I., Nishida, K., Kinoshita, S., Matsubara, K. and Okubo, K. Isolation and characterization of human cathepsin V: a major proteinase in corneal epithelium. Invest. Ophthalmol. Vis. Sci. 39 (1998) 1789–1796. [PMID: 9727401]
3.  Santamaría, I., Velasco, G., Cazorla, M., Fueyo, A., Campo, E. and López-Otín, C. Cathepsin L2, a novel human cysteine proteinase produced by breast and colorectal carcinomas. Cancer Res. 58 (1998) 1624–1630. [PMID: 9563472]
[EC 3.4.22.43 created 2000]
 
 
EC 3.4.22.44     
Accepted name: nuclear-inclusion-a endopeptidase
Reaction: Hydrolyses glutaminyl bonds, and activity is further restricted by preferences for the amino acids in P6 - P1′ that vary with the species of potyvirus, e.g. Glu-Xaa-Xaa-Tyr-Xaa-Gln┼(Ser or Gly) for the enzyme from tobacco etch virus. The natural substrate is the viral polyprotein, but other proteins and oligopeptides containing the appropriate consensus sequence are also cleaved.
Other name(s): potyvirus NIa protease
Comments: The potyviruses cause diseases in plants, and inclusion bodies appear in the host cell nuclei; protein a of the inclusion bodies is the endopeptidase. The enzyme finds practical use when encoded in vectors for the artificial expression of recombinant fusion proteins, since it can confer on them the capacity for autolytic cleavage. It is also reported that transgenic plants expressing the enzyme are resistant to viral infection. Type example of peptidase family C4.
References:
1.  Fellers, J.P., Collins, G.B. and Hunt, A.G. The NIa-proteinase of different plant potyviruses provides specific resistance to viral infection. Crop Sci. 38 (1998) 1309–1319.
2.  Kim, D.-H. and Choi, K.Y. Potyvirus NIa protease. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 721–723.
3.  Takahashi, T., Nakanishi, M., Yao, Y., Uyeda, I. and Serizawa, N. Direct formation of human interleukin-11 by cis-acting system of plant virus protease in Escherichia coli. Biosci. Biotechnol. Biochem. 62 (1998) 953–958. [PMID: 9648226]
4.  Kim, D.H., Hwang, D.C., Kang, B.H., Lew, J., Han, J.S., Song, B.O.D. and Choi, K.Y. Effects of internal cleavages and mutations in the C-terminal region of NIa protease of turnip mosaic potyvirus on the catalytic activity. Virology 226 (1996) 183–190. [PMID: 8955037]
[EC 3.4.22.44 created 2000]
 
 
EC 3.4.22.45     
Accepted name: helper-component proteinase
Reaction: Hydrolyses a Gly┼Gly bond at its own C-terminus, commonly in the sequence -Tyr-Xaa-Val-Gly┼Gly, in the processing of the potyviral polyprotein
Other name(s): HC-Pro
Comments: Known from many potyviruses. The helper component-proteinase of the tobacco etch virus is a multifunctional protein with several known activities: the N-terminal region is required for aphid transmission and efficient genome amplification, the central region is required for long-distance movement in plants, and the C-terminal domain has cysteine endopeptidase activity. Type example of peptidase family C6.
References:
1.  Kasschau, K.D. and Carrington, J.C. Requirement for HC-Pro processing during genome amplification of tobacco etch potyvirus. Virology 209 (1995) 268–273. [PMID: 7747479]
2.  Verchot, J. Potyvirus helper component proteinase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 677–679.
[EC 3.4.22.45 created 2001]
 
 
EC 3.4.22.46     
Accepted name: L-peptidase
Reaction: Autocatalytically cleaves itself from the polyprotein of the foot-and-mouth disease virus by hydrolysis of a Lys┼Gly bond, but then cleaves host cell initiation factor eIF-4G at bonds -Gly┼Arg- and -Lys┼Arg-
Comments: Best known from foot-and-mouth disease virus, but occurs in other aphthoviruses and cardioviruses. Destruction of initiation factor eIF-4G has the effect of shutting off host-cell protein synthesis while allowing synthesis of viral proteins to continue. The tertiary structure reveals a distant relationship to papain and, consistent with this, compound E-64 is inhibitory. Type example of peptidase family C28.
References:
1.  Piccone, M.E., Zellner, M., Kumosinski, T.F., Mason, P.W. and Grubman, M.J. Identification of the active-site residues of the L proteinase of foot-and-mouth disease virus. J. Virol. 69 (1995) 4950–4956. [PMID: 7609064]
2.  Guarné, A., Hampoelz, B., Glaser, W., Carpena, X., Torma, J., Fita, I. and Skern, T. Structural and biochemical features distinguish the foot-and-mouth disease virus leader proteinase from other papain-like enzymes. J. Mol. Biol. 302 (2000) 1227–1240. [PMID: 11183785]
[EC 3.4.22.46 created 2001]
 
 
EC 3.4.22.47     
Accepted name: gingipain K
Reaction: Endopeptidase with strict specificity for lysyl bonds
Other name(s): Lys-gingipain; PrtP proteinase
Comments: Activity is stimulated by glycine. Known from the bacterium Porphyromonas gingivalis and contributes to the pathogenicity of the organism. In peptidase family C25.
References:
1.  Pike, R., McGraw, W., Potempa, J. and Travis, J. Lysine- and arginine-specific proteinases from Porphyromonas gingivalis. Isolation, characterization, and evidence for the existence of complexes with hemagglutinins. J. Biol. Chem. 269 (1994) 406–411. [PMID: 8276827]
2.  Curtis, M.A., Aduse, O.J., Rangarajan, M., Gallagher, A., Sterne, J.A., Reid, C.R., Evans, H.E. and Samuelsson, B. Attenuation of the virulence of Porphyromonas gingivalis by using a specific synthetic Kgp protease inhibitor 2. Infect. Immun. 70 (2002) 6968–6975. [PMID: 12438376]
[EC 3.4.22.47 created 2003]
 
 
EC 3.4.22.48     
Accepted name: staphopain
Reaction: Broad endopeptidase action on proteins including elastin, but rather limited hydrolysis of small-molecule substrates. Assays are conveniently made with hemoglobin, casein or Z-Phe-Arg-NHMec as substrate
Other name(s): staphylopain
Comments: Known from species of Staphylococcus. Type example of peptidase family C47.
References:
1.  Hofmann, B., Hecht, H.J., Kiess, M. and Schomburg, D. Crystal structure of a thiol proteinase from Staphylococcus aureus V8 in the E-64 inhibitor complex. Acta Crystallogr. Sect. A (Suppl.) 49 (1993) 102.
2.  Potempa, J., Dubin, A. and Travis, J. Staphylopain. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 669–671.
3.  Dubin, G., Chmiel, D., Mak, P., Rakwalska, M., Rzychon, M. and Dubin, A. Molecular cloning and biochemical characterisation of proteases from Staphylococcus epidermidis. Biol. Chem. 382 (2001) 1575–1582. [PMID: 11767947]
[EC 3.4.22.48 created 2003]
 
 
EC 3.4.22.49     
Accepted name: separase
Reaction: All bonds known to be hydrolysed by this endopeptidase have arginine in P1 and an acidic residue in P4. P6 is often occupied by an acidic residue or by an hydroxy-amino-acid residue, the phosphorylation of which enhances cleavage
Other name(s): separin
Comments: In both budding yeast and human cells, cleavage of the cohesin subunit Scc1 by separase is required for sister chromatid separation in mitosis. Budding yeast separase is also known to cleave the Rec8 subunit of a meiotic cohesin complex and the kinetochore protein Slk19. Type example of peptidase family C50.
References:
1.  Waizenegger, I., Gimenez-Abian, J., Wernic, D. and Peters, J. Regulation of human separase by securin binding and autocleavage. Curr. Biol. 12 (2002) 1368–1378. [PMID: 12194817]
[EC 3.4.22.49 created 2003]
 
 
EC 3.4.22.50     
Accepted name: V-cath endopeptidase
Reaction: Endopeptidase of broad specificity, hydrolyzing substrates of both cathepsin L and cathepsin B
Other name(s): AcNPV protease; BmNPV protease; NPV protease; baculovirus cathepsin; nucleopolyhedrosis virus protease; viral cathepsin
Comments: In peptidase family C1. Contributes to the liquefaction of the tissues of the insect host in the late stages of infection by the baculovirus.
References:
1.  Slack, J.M., Kuzio, J. and Faulkner, P. Characterization of V-cath, a cathepsin L-like proteinase expressed by the baculovirus Autographa californica multiple nuclear polyhedrosis-virus. J. Gen. Virol. 76 (1995) 1091–1098. [PMID: 7730794]
2.  Hawtin, R.E., Zarkowska, T., Arnold, K., Thomas, C.J., Gooday, G.W., King, L.A., Kuzio, J.A. and Possee, R.D. Liquefaction of Autographa californica nucleopolyhedrovirus-infected insects is dependent on the integrity of virus-encoded chitinase and cathepsin genes. Virology 238 (1997) 243–253. [PMID: 9400597]
[EC 3.4.22.50 created 2003]
 
 
EC 3.4.22.51     
Accepted name: cruzipain
Reaction: Broad endopeptidase specificity similar to that of cathepsin L
Other name(s): congopain; cruzain; evansain; trypanopain
Comments: In peptidase family C1. Is located in the digestive vacuoles of the parasitic trypanosome and contributes to the nutrition of the organism by digestion of host proteins.
References:
1.  Cazzulo, J.J., Stoka, V. and Turk, V. The major cysteine proteinase of Trypanosoma cruzi: a valid target for chemotherapy of Chagas disease. Curr. Pharm. Des. 7 (2001) 1143–1156. [PMID: 11472258]
[EC 3.4.22.51 created 2003]
 
 
EC 3.4.22.52     
Accepted name: calpain-1
Reaction: Broad endopeptidase specificity
Other name(s): μ-calpain; calcium-activated neutral protease I
Comments: In peptidase family C2. Requires Ca2+ at micromolar concentrations for activity. Cytosolic in animal cells. The active enzyme molecule is a heterodimer in which the large subunit contains the peptidase unit, and the small subunit is also a component of EC 3.4.22.53, calpain-2.
References:
1.  Dutt, P., Spriggs, C.N., Davies, P.L., Jia, Z. and Elce, J.S. Origins of the difference in Ca2+ requirement for activation of μ- and m-calpain. Biochem. J. 367 (2002) 263–269. [PMID: 12014988]
[EC 3.4.22.52 created 1981 as EC 3.4.22.17, transferred 2003 to EC 3.4.22.52]
 
 
EC 3.4.22.53     
Accepted name: calpain-2
Reaction: Broad endopeptidase specificity
Other name(s): calcium-activated neutral protease II; m-calpain; milli-calpain
Comments: Type example of peptidase family C2. Requires Ca2+ at millimolar concentrations for activity. Cytosolic in animal cells. The active enzyme molecule is a heterodimer in which the large subunit contains the peptidase unit, and the small subunit is also a component of EC 3.4.22.52, calpain-1.
References:
1.  Strobl, S., Fernandez-Catalan, C., Braun, M., Huber, R., Masumoto, H., Nakagawa, K., Irie, A., Sorimachi, H., Bourenkow, G., Bartunik, H., Suzuki, K. and Bode, W. The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium. Proc. Natl. Acad. Sci. USA 97 (2000) 588–592. [PMID: 10639123]
2.  Dutt, P., Spriggs, C.N., Davies, P.L., Jia, Z. and Elce, J.S. Origins of the difference in Ca2+ requirement for activation of μ- and m-calpain. Biochem. J. 367 (2002) 263–269. [PMID: 12014988]
[EC 3.4.22.53 created 1981 as EC 3.4.22.17, transferred 2003 to EC 3.4.22.53]
 
 
EC 3.4.22.54     
Accepted name: calpain-3
Reaction: Broad endopeptidase activity
Other name(s): p94; calpain p94; CAPN3; muscle calpain; calpain 3; calcium-activated neutral proteinase 3; muscle-specific calcium-activated neutral protease 3; CANP 3; calpain L3
Comments: This Ca2+-dependent enzyme is found in skeletal muscle and is genetically linked to limb girdle muscular dystrophy type 2A [1,4]. The enzyme is activated by autoproteolytic cleavage of insertion sequence 1 (IS1), which allows substrates and inhibitors gain access to the active site [4]. Substrates include the protein itself [3,4] and connectin/titin [2,5]. Belongs in peptidase family C2.
References:
1.  Sorimachi, H., Imajoh-Ohmi, S., Emori, Y., Kawasaki, H., Ohno, S., Minami, Y. and Suzuki, K. Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and μ-types. Specific expression of the mRNA in skeletal muscle. J. Biol. Chem. 264 (1989) 20106–20111. [PMID: 2555341]
2.  Sorimachi, H., Kinbara, K., Kimura, S., Takahashi, M., Ishiura, S., Sasagawa, N., Sorimachi, N., Shimada, H., Tagawa, K., Maruyama, K. and Suzuki, K. Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. J. Biol. Chem. 270 (1995) 31158–31162. [PMID: 8537379]
3.  Rey, M.A. and Davies, P.L. The protease core of the muscle-specific calpain, p94, undergoes Ca2+-dependent intramolecular autolysis. FEBS Lett. 532 (2002) 401–406. [PMID: 12482600]
4.  García Díaz, B.E., Gauthier, S. and Davies, P.L. Ca2+ dependency of calpain 3 (p94) activation. Biochemistry 45 (2006) 3714–3722. [PMID: 16533054]
5.  Ono, Y., Torii, F., Ojima, K., Doi, N., Yoshioka, K., Kawabata, Y., Labeit, D., Labeit, S., Suzuki, K., Abe, K., Maeda, T. and Sorimachi, H. Suppressed disassembly of autolyzing p94/CAPN3 by N2A connectin/titin in a genetic reporter system. J. Biol. Chem. 281 (2006) 18519–18531. [PMID: 16627476]
[EC 3.4.22.54 created 2007]
 
 
EC 3.4.22.55     
Accepted name: caspase-2
Reaction: Strict requirement for an Asp residue at P1, with Asp316 being essential for proteolytic activity and has a preferred cleavage sequence of Val-Asp-Val-Ala-Asp┼
Other name(s): ICH-1; NEDD-2; caspase-2L; caspase-2S; neural precursor cell expressed developmentally down-regulated protein 2; CASP-2; NEDD2 protein
Comments: Caspase-2 is an initiator caspase, as are caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63) [6]. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [6]. Two forms of caspase-2 with antagonistic effects exist: caspase-2L induces programmed cell death and caspase-2S suppresses cell death [2,3,5]. Caspase-2 is activated by caspase-3 (EC 3.4.22.56), or by a caspase-3-like protease. Activation involves cleavage of the N-terminal prodomain, followed by self-proteolysis between the large and small subunits of pro-caspase-2 and further proteolysis into smaller fragments [3]. Proteolysis occurs at Asp residues and the preferred substrate for this enzyme is a pentapeptide rather than a tetrapeptide [5]. Apart from itself, the enzyme can cleave golgin-16, which is present in the Golgi complex and has a cleavage site that is unique for caspase-2 [4,5]. αII-Spectrin, a component of the membrane cytoskeleton, is a substrate of the large isoform of pro-caspase-2 (caspase-2L) but not of the short isoform (caspase-2S). Belongs in peptidase family C14.
References:
1.  Kumar, S., Kinoshita, M., Noda, M., Copeland, N.G. and Jenkins, N.A. Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1β-converting enzyme. Genes Dev. 8 (1994) 1613–1626. [PMID: 7958843]
2.  Wang, L., Miura, M., Bergeron, L., Zhu, H. and Yuan, J. Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell 78 (1994) 739–750. [PMID: 8087842]
3.  Li, H., Bergeron, L., Cryns, V., Pasternack, M.S., Zhu, H., Shi, L., Greenberg, A. and Yuan, J. Activation of caspase-2 in apoptosis. J. Biol. Chem. 272 (1997) 21010–21017. [PMID: 9261102]
4.  Mancini, M., Machamer, C.E., Roy, S., Nicholson, D.W., Thornberry, N.A., Casciola-Rosen, L.A. and Rosen, A. Caspase-2 is localized at the Golgi complex and cleaves golgin-160 during apoptosis. J. Cell Biol. 149 (2000) 603–612. [PMID: 10791974]
5.  Zhivotovsky, B. and Orrenius, S. Caspase-2 function in response to DNA damage. Biochem. Biophys. Res. Commun. 331 (2005) 859–867. [PMID: 15865942]
6.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.55 created 2007]
 
 
EC 3.4.22.56     
Accepted name: caspase-3
Reaction: Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp┼ with a hydrophobic amino-acid residue at P2 and a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position
Other name(s): CPP32; apopain; yama protein
Comments: Caspase-3 is an effector/executioner caspase, as are caspase-6 (EC 3.4.22.59) and caspase-7 (EC 3.4.22.60) [5]. These caspases are responsible for the proteolysis of the majority of cellular polypeptides [e.g. poly(ADP-ribose) polymerase (PARP)], which leads to the apoptotic phenotype [3,5]. Procaspase-3 can be activated by caspase-1 (EC 3.4.22.36), caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63) as well as by the serine protease granzyme B [1]. Caspase-3 can activate procaspase-2 (EC 3.4.22.55) [2]. Activation occurs by inter-domain cleavage followed by removal of the N-terminal prodomain [6]. Although Asp-Glu-(Val/Ile)-Asp is thought to be the preferred cleavage sequence, the enzyme can accommodate different residues at P2 and P3 of the substrate [4]. Like caspase-2, a hydrophobic residue at P5 of caspase-3 leads to more efficient hydrolysis, e.g. (Val/Leu)-Asp-Val-Ala-Asp┼ is a better substrate than Asp-Val-Ala-Asp┼ . This is not the case for caspase-7 [4]. Belongs in peptidase family C14.
References:
1.  Krebs, J.F., Srinivasan, A., Wong, A.M., Tomaselli, K.J., Fritz, L.C. and Wu, J.C. Heavy membrane-associated caspase 3: identification, isolation, and characterization. Biochemistry 39 (2000) 16056–16063. [PMID: 11123933]
2.  Li, H., Bergeron, L., Cryns, V., Pasternack, M.S., Zhu, H., Shi, L., Greenberg, A. and Yuan, J. Activation of caspase-2 in apoptosis. J. Biol. Chem. 272 (1997) 21010–21017. [PMID: 9261102]
3.  Nicholson, D. and Thornberry, N.A. Caspase-3 and caspase-7. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1298–1302.
4.  Fang, B., Boross, P.I., Tozser, J. and Weber, I.T. Structural and kinetic analysis of caspase-3 reveals role for S5 binding site in substrate recognition. J. Mol. Biol. 360 (2006) 654–666. [PMID: 16781734]
5.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
6.  Martin, S.J., Amarante-Mendes, G.P., Shi, L., Chuang, T.H., Casiano, C.A., O'Brien, G.A., Fitzgerald, P., Tan, E.M., Bokoch, G.M., Greenberg, A.H. and Green, D.R. The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism. EMBO J. 15 (1996) 2407–2416. [PMID: 8665848]
[EC 3.4.22.56 created 2007]
 
 
EC 3.4.22.57     
Accepted name: caspase-4
Reaction: Strict requirement for Asp at the P1 position. It has a preferred cleavage sequence of Tyr-Val-Ala-Asp┼ but also cleaves at Asp-Glu-Val-Asp┼
Other name(s): ICErelII; ICErel-II; Ich-2; transcript X; TX; TX protease; caspase 4; CASP-4
Comments: This enzyme is part of the family of inflammatory caspases, which also includes caspase-1 (EC 3.4.22.36) and caspase-5 (EC 3.4.22.58) in humans and caspase-11 (EC 3.4.22.64), caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [3,5,6]. The enzyme is able to cleave itself and the p30 caspase-1 precursor, but, unlike caspase-1, it is very inefficient at generating mature interleukin-1β (IL-1β) from pro-IL-1β [1,4]. Both this enzyme and caspase-5 can cleave pro-caspase-3 to release the small subunit (p12) but not the large subunit (p17) [3]. The caspase-1 inhibitor Ac-Tyr-Val-Ala-Asp-CHO can also inhibit this enzyme, but more slowly [4]. Belongs in peptidase family C14.
References:
1.  Faucheu, C., Diu, A., Chan, A.W., Blanchet, A.M., Miossec, C., Hervé, F., Collard-Dutilleul, V., Gu, Y., Aldape, R.A., Lippke, J.A., Rocher, C., Su, M.S.-S., Livingston, D.J., Hercend, T. and Lalanne, J.-L. A novel human protease similar to the interleukin-1β converting enzyme induces apoptosis in transfected cells. EMBO J. 14 (1995) 1914–1922. [PMID: 7743998]
2.  Kamens, J., Paskind, M., Hugunin, M., Talanian, R.V., Allen, H., Banach, D., Bump, N., Hackett, M., Johnston, C.G., Li, P., Mankovich, J.A., Terranova, M. and Ghayur, T. Identification and characterization of ICH-2, a novel member of the interleukin-1β-converting enzyme family of cysteine proteases. J. Biol. Chem. 270 (1995) 15250–15256. [PMID: 7797510]
3.  Kamada, S., Funahashi, Y. and Tsujimoto, Y. Caspase-4 and caspase-5, members of the ICE/CED-3 family of cysteine proteases, are CrmA-inhibitable proteases. Cell Death Differ. 4 (1997) 473–478. [PMID: 16465268]
4.  Fassy, F., Krebs, O., Rey, H., Komara, B., Gillard, C., Capdevila, C., Yea, C., Faucheu, C., Blanchet, A.M., Miossec, C. and Diu-Hercend, A. Enzymatic activity of two caspases related to interleukin-1β-converting enzyme. Eur. J. Biochem. 253 (1998) 76–83. [PMID: 9578463]
5.  Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561–574. [PMID: 15163405]
6.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.57 created 2007]
 
 
EC 3.4.22.58     
Accepted name: caspase-5
Reaction: Strict requirement for Asp at the P1 position. It has a preferred cleavage sequence of Tyr-Val-Ala-Asp┼ but also cleaves at Asp-Glu-Val-Asp┼
Other name(s): ICErel-III; Ich-3; ICH-3 protease; transcript Y; TY; CASP-5
Comments: This enzyme is part of the family of inflammatory caspases, which also includes caspase-1 (EC 3.4.22.36) and caspase-4 (EC 3.4.22.57) in humans and caspase-11 (EC 3.4.22.64), caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [3,5,6]. The enzyme is able to cleave itself and the p30 caspase-1 precursor, but is very inefficient at generating mature interleukin-1β (IL-1β) from pro-IL-1β [1,4]. Both this enzyme and caspase-4 can cleave pro-caspase-3 to release the small subunit (p12) but not the large subunit (p17) [3]. Unlike caspase-4, this enzyme can be induced by lipopolysaccharide [3]. Belongs in peptidase family C14.
References:
1.  Faucheu, C., Blanchet, A.M., Collard-Dutilleul, V., Lalanne, J.L. and Diu-Hercend, A. Identification of a cysteine protease closely related to interleukin-1 β-converting enzyme. Eur. J. Biochem. 236 (1996) 207–213. [PMID: 8617266]
2.  Kamada, S., Funahashi, Y. and Tsujimoto, Y. Caspase-4 and caspase-5, members of the ICE/CED-3 family of cysteine proteases, are CrmA-inhibitable proteases. Cell Death Differ. 4 (1997) 473–478. [PMID: 16465268]
3.  Lin, X.Y., Choi, M.S. and Porter, A.G. Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-γ. J. Biol. Chem. 275 (2000) 39920–39926. [PMID: 10986288]
4.  Fassy, F., Krebs, O., Rey, H., Komara, B., Gillard, C., Capdevila, C., Yea, C., Faucheu, C., Blanchet, A.M., Miossec, C. and Diu-Hercend, A. Enzymatic activity of two caspases related to interleukin-1β-converting enzyme. Eur. J. Biochem. 253 (1998) 76–83. [PMID: 9578463]
5.  Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561–574. [PMID: 15163405]
6.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.58 created 2007]
 
 
EC 3.4.22.59     
Accepted name: caspase-6
Reaction: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Val-Glu-His-Asp┼
Other name(s): CASP-6; apoptotic protease Mch-2; Mch2
Comments: Caspase-6 is an effector/executioner caspase, as are caspase-3 (EC 3.4.22.56) and caspase-7 (EC 3.4.22.60) [2]. These caspases are responsible for the proteolysis of the majority of cellular polypeptides [e.g. poly(ADP-ribose) polymerase (PARP)], which leads to the apoptotic phenotype [2]. Caspase-6 can cleave its prodomain to produce mature caspase-6, which directly activates caspase-8 (EC 3.4.22.61) and leads to the release of cytochrome c from the mitochondria. The release of cytochrome c is an essential component of the intrinsic apoptosis pathway [1]. The enzyme can also cleave and inactivate lamins, the intermediate filament scaffold proteins of the nuclear envelope, leading to nuclear fragmentation in the final phases of apoptosis [2,4,5,6]. Belongs in peptidase family C14.
References:
1.  Cowling, V. and Downward, J. Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ. 9 (2002) 1046–1056. [PMID: 12232792]
2.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
3.  Kang, B.H., Ko, E., Kwon, O.K. and Choi, K.Y. The structure of procaspase 6 is similar to that of active mature caspase 6. Biochem. J. 364 (2002) 629–634. [PMID: 12049625]
4.  Lee, S.C., Chan, J., Clement, M.V. and Pervaiz, S. Functional proteomics of resveratrol-induced colon cancer cell apoptosis: caspase-6-mediated cleavage of lamin A is a major signaling loop. Proteomics 6 (2006) 2386–2394. [PMID: 16518869]
5.  MacLachlan, T.K. and El-Deiry, W.S. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc. Natl. Acad. Sci. USA 99 (2002) 9492–9497. [PMID: 12089322]
6.  Takahashi, A., Alnemri, E.S., Lazebnik, Y.A., Fernandes-Alnemri, T., Litwack, G., Moir, R.D., Goldman, R.D., Poirier, G.G., Kaufmann, S.H. and Earnshaw, W.C. Cleavage of lamin A by Mch2α but not CPP32: multiple interleukin 1β-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc. Natl. Acad. Sci. USA 93 (1996) 8395–8400. [PMID: 8710882]
[EC 3.4.22.59 created 2007]
 
 
EC 3.4.22.60     
Accepted name: caspase-7
Reaction: Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Asp-Glu-Val-Asp┼
Other name(s): CASP-7; ICE-like apoptotic protease 3; ICE-LAP3; apoptotic protease Mch-3; Mch3; CMH-1
Comments: Caspase-7 is an effector/executioner caspase, as are caspase-3 (EC 3.4.22.56) and caspase-6 (EC 3.4.22.59) [1]. These caspases are responsible for the proteolysis of the majority of cellular polypeptides [e.g. poly(ADP-ribose) polymerase (PARP)], which leads to the apoptotic phenotype [2]. Although a hydrophobic residue at P5 of caspase-2 (EC 3.4.22.55) and caspase-3 leads to more efficient hydrolysis, the amino-acid residue at this location in caspase-7 has no effect [3]. Caspase-7 is activated by the initiator caspases [caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63)]. Removal of the N-terminal prodomain occurs before cleavage in the linker region between the large and small subunits [4]. Belongs in peptidase family C14.
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Nicholson, D. and Thornberry, N.A. Caspase-3 and caspase-7. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1298–1302.
3.  Fang, B., Boross, P.I., Tozser, J. and Weber, I.T. Structural and kinetic analysis of caspase-3 reveals role for S5 binding site in substrate recognition. J. Mol. Biol. 360 (2006) 654–666. [PMID: 16781734]
4.  Denault, J.B. and Salvesen, G.S. Human caspase-7 activity and regulation by its N-terminal peptide. J. Biol. Chem. 278 (2003) 34042–34050. [PMID: 12824163]
[EC 3.4.22.60 created 2007]
 
 
EC 3.4.22.61     
Accepted name: caspase-8
Reaction: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp┼(Gly/Ser/Ala)
Other name(s): FLICE, FADD-like ICE; MACH; MORT1-associated CED-3 homolog; Mch5; mammalian Ced-3 homolog 5; CASP-8; ICE-like apoptotic protease 5; FADD-homologous ICE/CED-3-like protease; apoptotic cysteine protease; apoptotic protease Mch-5; CAP4
Comments: Caspase-8 is an initiator caspase, as are caspase-2 (EC 3.4.22.55), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63) [1]. Caspase-8 is the apical activator of the extrinsic (death receptor) apoptosis pathway, triggered by death receptor ligation [2]. It contains two tandem death effector domains (DEDs) in its N-terminal prodomain, and these play a role in procaspase activation [1]. This enzyme is linked to cell surface death receptors such as Fas [1,5]. When Fas is aggregated by the Fas ligand, procaspase-8 is recruited to the death receptor where it is activated [1]. The enzyme has a preference for Glu at P3 and prefers small residues, such as Gly, Ser and Ala, at the P1′ position. It has very broad P4 specificity, tolerating substrates with Asp, Val or Leu in this position [2,3,4]. Endogenous substrates for caspase-8 include procaspase-3, the pro-apoptotic Bcl-2 family member Bid, RIP, PAK2 and the caspase-8 activity modulator FLIPL [4,5]. Belongs in peptidase family C14.
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Boldin, M.P., Goncharov, T.M., Goltsev, Y.V. and Wallach, D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85 (1996) 803–815. [PMID: 8681376]
3.  Muzio, M., Chinnaiyan, A.M., Kischkel, F.C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J.D., Zhang, M., Gentz, R., Mann, M., Krammer, P.H., Peter, M.E. and Dixit, V.M. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85 (1996) 817–827. [PMID: 8681377]
4.  Salvesen, G.S. and Boatright, K.M. Caspase-8. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1293–1296.
5.  Fischer, U., Stroh, C. and Schulze-Osthoff, K. Unique and overlapping substrate specificities of caspase-8 and caspase-10. Oncogene 25 (2006) 152–159. [PMID: 16186808]
6.  Blanchard, H., Donepudi, M., Tschopp, M., Kodandapani, L., Wu, J.C. and Grütter, M.G. Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex. J. Mol. Biol. 302 (2000) 9–16. [PMID: 10964557]
7.  Boatright, K.M., Deis, C., Denault, J.B., Sutherlin, D.P. and Salvesen, G.S. Activation of caspases-8 and -10 by FLIPL. Biochem. J. 382 (2004) 651–657. [PMID: 15209560]
[EC 3.4.22.61 created 2007]
 
 
EC 3.4.22.62     
Accepted name: caspase-9
Reaction: Strict requirement for an Asp residue at position P1 and with a marked preference for His at position P2. It has a preferred cleavage sequence of Leu-Gly-His-Asp┼Xaa
Other name(s): CASP-9; ICE-like apoptotic protease 6; ICE-LAP6; apoptotic protease Mch-6; apoptotic protease-activating factor 3; APAF-3
Comments: Caspase-9 is an initiator caspase, as are caspase -2 (EC 3.4.22.55), caspase-8 (EC 3.4.22.61) and caspase-10 (EC 3.4.22.63) [1]. Caspase-9 contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [1]. An alternatively spliced version of caspase-9 also exists, caspase-9S, that inhibits apoptosis, similar to the situation found with caspase-2 [1]. Phosphorylation of caspase-9 from some species by Akt, a serine-threonine protein kinase, inhibits caspase activity in vitro and caspase activation in vivo [1]. The activity of caspase-9 is increased dramatically upon association with the apoptosome but the enzyme can be activated without proteolytic cleavage [2,3]. Procaspase-3 is the enzyme’s physiological substrate [2]. Belongs in peptidase family C14.
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Yin, Q., Park, H.H., Chung, J.Y., Lin, S.C., Lo, Y.C., da Graca, L.S., Jiang, X. and Wu, H. Caspase-9 holoenzyme is a specific and optimal procaspase-3 processing machine. Mol. Cell. 22 (2006) 259–268. [PMID: 16630893]
3.  Boatright, K.M., Renatus, M., Scott, F.L., Sperandio, S., Shin, H., Pedersen, I.M., Ricci, J.E., Edris, W.A., Sutherlin, D.P., Green, D.R. and Salvesen, G.S. A unified model for apical caspase activation. Mol. Cell. 11 (2003) 529–541. [PMID: 12620239]
4.  Salvesen, G.S. and Boatright, K.M. Caspase-9. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1296–1298.
[EC 3.4.22.62 created 2007]
 
 
EC 3.4.22.63     
Accepted name: caspase-10
Reaction: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Leu-Gln-Thr-Asp┼Gly
Other name(s): FLICE2, Mch4; CASP-10; ICE-like apoptotic protease 4; apoptotic protease Mch-4; FAS-associated death domain protein interleukin-1β-converting enzyme 2
Comments: Caspase-10 is an initiator caspase, as are caspase-2 (EC 3.4.22.55), caspase-8 (EC 3.4.22.61) and caspase-9 (EC 3.4.22.62) [1]. Like caspase-8, caspase-10 contains two tandem death effector domains (DEDs) in its N-terminal prodomain, and these play a role in procaspase activation [1]. The enzyme has many overlapping substrates in common with caspase-8, such as RIP (the cleavage of which impairs NF-κB survival signalling and starts the cell-death process) and PAK2 (associated with some of the morphological features of apoptosis, such as cell rounding and apoptotic body formation) [2]. Bid, a Bcl2 protein, can be cleaved by caspase-3 (EC 3.4.22.56), caspase-8 and caspase-10 at Lys-Gln-Thr-Asp┼ to yield the pro-apoptotic p15 fragment. The p15 fragment is N-myristoylated and enhances the release of cytochrome c from mitochondria (which, in turn, initiatiates the intrinsic apoptosis pathway). Bid can be further cleaved by caspase-10 and granzyme B but not by caspase-3 or caspase-8 at Ile-Glu-Thr-Asp┼ to yield a p13 fragment that is not N-myristoylated [2]. Belongs in peptidase family C14.
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Fischer, U., Stroh, C. and Schulze-Osthoff, K. Unique and overlapping substrate specificities of caspase-8 and caspase-10. Oncogene 25 (2006) 152–159. [PMID: 16186808]
3.  Shikama, Y., Yamada, M. and Miyashita, T. Caspase-8 and caspase-10 activate NF-κB through RIP, NIK and IKKα kinases. Eur. J. Immunol. 33 (2003) 1998–2006. [PMID: 12884866]
4.  Boatright, K.M., Deis, C., Denault, J.B., Sutherlin, D.P. and Salvesen, G.S. Activation of caspases-8 and -10 by FLIPL. Biochem. J. 382 (2004) 651–657. [PMID: 15209560]
[EC 3.4.22.63 created 2007]
 
 
EC 3.4.22.64     
Accepted name: caspase-11
Reaction: Strict requirement for Asp at the P1 position and has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp┼
Other name(s): CASP-11
Comments: This murine enzyme is part of the family of inflammatory caspases, which also includes caspase-1 (EC 3.4.22.36), caspase-4 (EC 3.4.22.57) and caspase-5 (EC 3.4.22.58) in humans and caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation. Like caspase-5, but unlike caspase-4, this enzyme can be induced by lipopolysaccharide [1]. This enzyme not only activates caspase-1, which is required for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, but it also activates caspase-3 (EC 3.4.22.56), which leads to cellular apoptosis under pathological conditions [1,2]. Belongs in peptidase family C14.
References:
1.  Kang, S.J., Wang, S., Hara, H., Peterson, E.P., Namura, S., Amin-Hanjani, S., Huang, Z., Srinivasan, A., Tomaselli, K.J., Thornberry, N.A., Moskowitz, M.A. and Yuan, J. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell. Biol. 149 (2000) 613–622. [PMID: 10791975]
2.  Hur, J., Kim, S.Y., Kim, H., Cha, S., Lee, M.S. and Suk, K. Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway. FEBS Lett. 507 (2001) 157–162. [PMID: 11684090]
3.  Wang, S., Miura, M., Jung, Y.K., Zhu, H., Li, E. and Yuan, J. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92 (1998) 501–509. [PMID: 9491891]
4.  Endo, M., Mori, M., Akira, S. and Gotoh, T. C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. J. Immunol. 176 (2006) 6245–6253. [PMID: 16670335]
5.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.64 created 2007]
 
 
EC 3.4.22.65     
Accepted name: peptidase 1 (mite)
Reaction: Broad endopeptidase specificity
Other name(s): allergen Der f 1; allergen Der p 1; antigen Der p 1; antigen Eur m 1; antigen Pso o 1; major mite fecal allergen Der p 1; Der p 1; Der f 1; Eur m 1; endopeptidase 1 (mite)
Comments: This enzyme, derived from the house dust mite, is a major component of the allergic immune response [2]. The substrate specificity of this enzyme is not altogether clear. It cleaves the low-affinity IgE receptor CD23 at Glu298┼Ser299 and Ser155┼Ser156 [1]. It also cleaves the pulmonary structural proteins occludin and claudin at Leu┼Leu, Asp┼Leu and at Gly┼Thr bonds [1,2]. It can also cleave the α subunit of the interleukin-2 (IL-2) receptor (CD25) [4]. Using a positional scanning combinatorial library, it was found that the major substrate-specificity determinant is for Ala in the P2 position [3]. The enzyme shows only a slight preference for basic amino acids in the P1 and P3 positions and a preference for aliphatic amino acids such as Ile, Pro, Val, Leu and norleucine in the P4 position [3]. Belongs in peptidase family C1A.
References:
1.  Meighan, P. and Pirzad, R. Mite endopeptidase 1. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1187–1189.
2.  Kalsheker, N.A., Deam, S., Chambers, L., Sreedharan, S., Brocklehurst, K. and Lomas, D.A. The house dust mite allergen Der p1 catalytically inactivates α1-antitrypsin by specific reactive centre loop cleavage: a mechanism that promotes airway inflammation and asthma. Biochem. Biophys. Res. Commun. 221 (1996) 59–61. [PMID: 8660343]
3.  Harris, J., Mason, D.E., Li, J., Burdick, K.W., Backes, B.J., Chen, T., Shipway, A., Van Heeke, G., Gough, L., Ghaemmaghami, A., Shakib, F., Debaene, F. and Winssinger, N. Activity profile of dust mite allergen extract using substrate libraries and functional proteomic microarrays. Chem. Biol. 11 (2004) 1361–1372. [PMID: 15489163]
4.  Schulz, O., Sewell, H.F. and Shakib, F. Proteolytic cleavage of CD25, the α subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J. Exp. Med. 187 (1998) 271–275. [PMID: 9432986]
5.  Schulz, O., Sewell, H.F. and Shakib, F. A sensitive fluorescent assay for measuring the cysteine protease activity of Der p 1, a major allergen from the dust mite Dermatophagoides pteronyssinus. Mol. Pathol. 51 (1998) 222–224. [PMID: 9893750]
6.  Takai, T., Kato, T., Sakata, Y., Yasueda, H., Izuhara, K., Okumura, K. and Ogawa, H. Recombinant Der p 1 and Der f 1 exhibit cysteine protease activity but no serine protease activity. Biochem. Biophys. Res. Commun. 328 (2005) 944–952. [PMID: 15707969]
[EC 3.4.22.65 created 2007]
 
 
EC 3.4.22.66     
Accepted name: calicivirin
Reaction: Endopeptidase with a preference for cleavage when the P1 position is occupied by Glu┼ and the P1′ position is occupied by Gly┼
Other name(s): Camberwell virus processing peptidase; Chiba virus processing peptidase; Norwalk virus processing peptidase; Southampton virus processing peptidase; Southampton virus; norovirus virus processing peptidase; calicivirus trypsin-like cysteine protease; calicivirus TCP; calicivirus 3C-like protease; calicivirus endopeptidase; rabbit hemorrhagic disease virus 3C endopeptidase
Comments: Viruses that are members of the Norovirus genus (Caliciviridae family) are a major cause of epidemic acute viral gastroenteritis [4]. The nonstructural proteins of these viruses are produced by proteolytic cleavage of a large precursor polyprotein, performed by a protease that is incorporated into the polyprotein [6]. Cleavage sites are apparently defined by features based on both sequence and structure since several sites in the polyprotein fulfilling the identified sequence requirements are not cleaved [1]. The presence of acidic (Asp), basic (Arg), aromatic (Tyr) or aliphatic (Leu) amino acids at the P1′ position results in only minor differences in cleavage efficiency, suggesting that steric or conformational constraints may play a role in determining specificity [1]. Changes to the amino acid at the P2 position do not alter cleavage efficiency [1,2]. Belongs in peptidase family C37.
References:
1.  Meyers, G., Rossi, C. and Thiel, H.J. Calicivirus endopeptidases. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1380–1382.
2.  Wirblich, C., Sibilia, M., Boniotti, M.B., Rossi, C., Thiel, H.J. and Meyers, G. 3C-like protease of rabbit hemorrhagic disease virus: identification of cleavage sites in the ORF1 polyprotein and analysis of cleavage specificity. J. Virol. 69 (1995) 7159–7168. [PMID: 7474137]
3.  Martín Alonso, J.M., Casais, R., Boga, J.A. and Parra, F. Processing of rabbit hemorrhagic disease virus polyprotein. J. Virol. 70 (1996) 1261–1265. [PMID: 8551592]
4.  Liu, B., Clarke, I.N. and Lambden, P.R. Polyprotein processing in Southampton virus: identification of 3C-like protease cleavage sites by in vitro mutagenesis. J. Virol. 70 (1996) 2605–2610. [PMID: 8642693]
5.  Liu, B.L., Viljoen, G.J., Clarke, I.N. and Lambden, P.R. Identification of further proteolytic cleavage sites in the Southampton calicivirus polyprotein by expression of the viral protease in E. coli. J. Gen. Virol. 80 (1999) 291–296. [PMID: 10073687]
[EC 3.4.22.66 created 2007]
 
 
EC 3.4.22.67     
Accepted name: zingipain
Reaction: Preferential cleavage of peptides with a proline residue at the P2 position
Other name(s): ginger protease; GP-I; GP-II; ginger protease II (Zingiber officinale); zingibain
Comments: This enzyme is found in ginger (Zingiber officinale) rhizome and is a member of the papain family. GP-II contains two glycosylation sites. The enzyme is inhibited by some divalent metal ions, such as Hg2+, Cu2+, Cd2+ and Zn2+ [2]. Belongs in peptidase family C1.
References:
1.  Choi, K.H. and Laursen, R.A. Amino-acid sequence and glycan structures of cysteine proteases with proline specificity from ginger rhizome Zingiber officinale. Eur. J. Biochem. 267 (2000) 1516–1526. [PMID: 10691991]
2.  Ohtsuki, K., Taguchi, K., Sato, K. and Kawabata, M. Purification of ginger proteases by DEAE-Sepharose and isoelectric focusing. Biochim. Biophys. Acta 1243 (1995) 181–184. [PMID: 7873561]
3.  Choi, K.H., Laursen, R.A. and Allen, K.N. The 2.1 Å structure of a cysteine protease with proline specificity from ginger rhizome, Zingiber officinale. Biochemistry 38 (1999) 11624–11633. [PMID: 10512617]
[EC 3.4.22.67 created 2007]
 
 
EC 3.4.22.68     
Accepted name: Ulp1 peptidase
Reaction: Hydrolysis of the α-linked peptide bond in the sequence Gly-Gly┼Ala-Thr-Tyr at the C-terminal end of the small ubiquitin-like modifier (SUMO) propeptide, Smt3, leading to the mature form of the protein. A second reaction involves the cleavage of an ε-linked peptide bond between the C-terminal glycine of the mature SUMO and the lysine ε-amino group of the target protein
Other name(s): Smt3-protein conjugate proteinase; Ubl-specific protease 1; Ulp1; Ulp1 endopeptidase; Ulp1 protease
Comments: The enzyme from Saccharomyces cerevisiae can also recognize small ubiquitin-like modifier 1 (SUMO-1) from human as a substrate in both SUMO-processing (α-linked peptide bonds) and SUMO-deconjugation (ε-linked peptide bonds) reactions [1,2,3]. Ulp1 has several functions, including an essential role in chromosomal segregation and progression of the cell cycle through the G2/M phase of the cell cycle. Belongs in peptidase family C48.
References:
1.  Lima, C.D. Ulp1 endopeptidase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1340–1344.
2.  Li, S.-J. and Hochstrasser, M. A new protease required for cell-cycle progression in yeast. Nature 398 (1999) 246–251. [PMID: 10094048]
3.  Taylor, D.L., Ho, J.C., Oliver, A. and Watts, F.Z. Cell-cycle-dependent localisation of Ulp1, a Schizosaccharomyces pombe Pmt3 (SUMO)-specific protease. J. Cell Sci. 115 (2002) 1113–1122. [PMID: 11884512]
4.  Li, S.-J. and Hochstrasser, M. The Ulp1 SUMO isopeptidase: distinct domains required for viability, nuclear envelope localization, and substrate specificity. J. Cell Biol. 160 (2003) 1069–1081. [PMID: 12654900]
5.  Ihara, M., Koyama, H., Uchimura, Y., Saitoh, H. and Kikuchi, A. Noncovalent binding of small ubiquitin-related modifier (SUMO) protease to SUMO is necessary for enzymatic activities and cell growth. J. Biol. Chem. 282 (2007) 16465–16475. [PMID: 17428805]
6.  Mukhopadhyay, D. and Dasso, M. Modification in reverse: the SUMO proteases. Trends Biochem. Sci. 32 (2007) 286–295. [PMID: 17499995]
[EC 3.4.22.68 created 2008, modified 2011]
 
 
EC 3.4.22.69     
Accepted name: SARS coronavirus main proteinase
Reaction: TSAVLQ┼SGFRK-NH2 and SGVTFQ┼GKFKK the two peptides corresponding to the two self-cleavage sites of the SARS 3C-like proteinase are the two most reactive peptide substrates. The enzyme exhibits a strong preference for substrates containing Gln at P1 position and Leu at P2 position.
Other name(s): 3cLpro; 3C-like protease; coronavirus 3C-like protease; Mpro; SARS 3C-like protease; SARS coronavirus 3CL protease; SARS coronavirus main peptidase; SARS coronavirus main protease; SARS-CoV 3CLpro enzyme; SARS-CoV main protease; SARS-CoV Mpro; severe acute respiratory syndrome coronavirus main protease
Comments: SARS coronavirus main protease is the key enzyme in SARS coronavirus replicase polyprotein processing. In peptidase family C30.
References:
1.  Goetz, D.H., Choe, Y., Hansell, E., Chen, Y.T., McDowell, M., Jonsson, C.B., Roush, W.R., McKerrow, J. and Craik, C.S. Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus. Biochemistry 46 (2007) 8744–8752. [PMID: 17605471]
2.  Fan, K., Wei, P., Feng, Q., Chen, S., Huang, C., Ma, L., Lai, B., Pei, J., Liu, Y., Chen, J. and Lai, L. Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase. J. Biol. Chem. 279 (2004) 1637–1642. [PMID: 14561748]
3.  Akaji, K., Konno, H., Onozuka, M., Makino, A., Saito, H. and Nosaka, K. Evaluation of peptide-aldehyde inhibitors using R188I mutant of SARS 3CL protease as a proteolysis-resistant mutant. Bioorg. Med. Chem. 16 (2008) 9400–9408. [PMID: 18845442]
[EC 3.4.22.69 created 2009]
 
 
EC 3.4.22.70     
Accepted name: sortase A
Reaction: The enzyme catalyses a cell wall sorting reaction in which a surface protein with a sorting signal containing a LPXTG motif is cleaved between the Thr and Gly residue. The resulting threonine carboxyl end of the protein is covalently attached to a pentaglycine cross-bridge of peptidoglycan.
Other name(s): SrtA; SrtA protein; SrtA sortase
Comments: In peptidase family C60.
References:
1.  Ton-That, H., Liu, G., Mazmanian, S.K., Faull, K.F. and Schneewind, O. Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif. Proc. Natl. Acad. Sci. USA 96 (1999) 12424–12429. [PMID: 10535938]
2.  Zong, Y., Bice, T.W., Ton-That, H., Schneewind, O. and Narayana, S.V. Crystal structures of Staphylococcus aureus sortase A and its substrate complex. J. Biol. Chem. 279 (2004) 31383–31389. [PMID: 15117963]
3.  Race, P.R., Bentley, M.L., Melvin, J.A., Crow, A., Hughes, R.K., Smith, W.D., Sessions, R.B., Kehoe, M.A., McCafferty, D.G. and Banfield, M.J. Crystal structure of Streptococcus pyogenes sortase A: implications for sortase mechanism. J. Biol. Chem. 284 (2009) 6924–6933. [PMID: 19129180]
[EC 3.4.22.70 created 2009]
 
 
EC 3.4.22.71     
Accepted name: sortase B
Reaction: The enzyme catalyses a cell wall sorting reaction in which a surface protein with a sorting signal containing a NXTN motif is cleaved. The resulting threonine carboxyl end of the protein is covalently attached to a pentaglycine cross-bridge of peptidoglycan.
Other name(s): SrtB
Comments: In peptidase family C60.
References:
1.  Zong, Y., Mazmanian, S.K., Schneewind, O. and Narayana, S.V. The structure of sortase B, a cysteine transpeptidase that tethers surface protein to the Staphylococcus aureus cell wall. Structure 12 (2004) 105–112. [PMID: 14725770]
2.  Bierne, H., Garandeau, C., Pucciarelli, M.G., Sabet, C., Newton, S., Garcia-del Portillo, F., Cossart, P. and Charbit, A. Sortase B, a new class of sortase in Listeria monocytogenes. J. Bacteriol. 186 (2004) 1972–1982. [PMID: 15028680]
[EC 3.4.22.71 created 2009]
 
 
EC 3.4.23.1     
Accepted name: pepsin A
Reaction: Preferential cleavage: hydrophobic, preferably aromatic, residues in P1 and P1′ positions. Cleaves Phe1┼Val, Gln4┼His, Glu13┼Ala, Ala14┼Leu, Leu15┼Tyr, Tyr16┼Leu, Gly23┼Phe, Phe24┼Phe and Phe25┼Tyr bonds in the B chain of insulin
Other name(s): pepsin; lactated pepsin; pepsin fortior; fundus-pepsin; elixir lactate of pepsin; P I; lactated pepsin elixir; P II; pepsin R; pepsin D
Comments: The predominant endopeptidase in the gastric juice of vertebrates, formed from pepsinogen A by limited proteolysis. Human pepsin A occurs in five molecular forms. Pig pepsin D [1,2] is unphosphorylated pepsin A. Type example of peptidase family A1.
References:
1.  Lee, D. and Ryle, A.P. Pepsinogen D. A fourth proteolytic zymogen from pig gastric mucosa. Biochem. J. 104 (1967) 735–741. [PMID: 4167464]
2.  Lee, D. and Ryle, A.P. Pepsin D. A minor component of commercial pepsin preparations. Biochem. J. 104 (1967) 742–748. [PMID: 4860638]
3.  Foltmann, R. Gastric proteinases -structure, function, evolution and mechanism of action. Essays Biochem. 17 (1981) 52–84. [PMID: 6795036]
4.  James, M.N.G. and Sielecki, A.R. Molecular structure of an aspartic proteinase zymogen, porcine pepsinogen, at 1.8 Å resolution. Nature 319 (1986) 33–38. [PMID: 3941737]
5.  Fruton, J.S. Aspartyl proteinases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 1–38.
6.  Tang, J. and Wong, R.N.S. Evolution in the structure and function of aspartic proteases. J. Cell. Biochem. 33 (1987) 53–63. [PMID: 3546346]
7.  Pohl, J. and Dunn, B.M. Secondary enzyme-substrate interactions: kinetic evidence for ionic interactions between substrate side chains and the pepsin active site. Biochemistry 27 (1988) 4827–4834. [PMID: 3139029]
[EC 3.4.23.1 created 1961 as EC 3.4.4.1, transferred 1972 to EC 3.4.23.1, modified 1986, modified 1989]
 
 
EC 3.4.23.2     
Accepted name: pepsin B
Reaction: Degradation of gelatin; little activity on hemoglobin. Specificity on B chain of insulin more restricted than that of pepsin A; does not cleave at Phe1-Val, Gln4-His or Gly23-Phe
Other name(s): parapepsin I; pig gelatinase
Comments: Formed from pig pepsinogen B. In peptidase family A1 (pepsin A family)
References:
1.  Ryle, A.P. The porcine pepsins and pepsinogens. Methods Enzymol. 19 (1970) 316–336.
[EC 3.4.23.2 created 1961 as EC 3.4.4.2, transferred 1972 to EC 3.4.23.2, modified 1986]
 
 
EC 3.4.23.3     
Accepted name: gastricsin
Reaction: More restricted specificity than pepsin A, but shows preferential cleavage at Tyr┼ bonds. High activity on hemoglobin
Other name(s): pepsin C; pig parapepsin II; parapepsin II
Comments: Formed from progastricsin, apparently in the gastric juice of most vertebrates. In addition to the fundus, progastricsin is also secreted in antrum and proximal duodenum. Seminal plasma contains a zymogen that is immunologically identical with progastricsin [6]. In peptidase family A1 (pepsin A family).
References:
1.  Ryle, A.P. The porcine pepsins and pepsinogens. Methods Enzymol. 19 (1970) 316–336.
2.  Tang, J. Gastricsin and pepsin. Methods Enzymol. 19 (1970) 406–421.
3.  Foltmann, B. Gastric proteinases - structure, function, evolution and mechanism of action. Essays Biochem. 17 (1981) 52–84. [PMID: 6795036]
4.  Foltmann, B. and Jensen, A.L. Human progastricsin - analysis of intermediates during activation into gastricsin and determination of the amino-acid sequence of the propart. Eur. J. Biochem. 128 (1982) 63–70. [PMID: 6816595]
5.  Martin, P., Trieu-Cuot, P., Collin, J.-C. and Ribadeau Dumas, B. Purification and characterization of bovine gastricsin. Eur. J. Biochem. 122 (1982) 31–39. [PMID: 6800788]
6.  Reid, W.A., Vongsorasak, L., Svasti, J., Valler, M.J. and Kay, J. Identification of the acid proteinase in human seminal fluid as a gastricsin originating in the prostate. Cell Tissue Res. 236 (1984) 597–600. [PMID: 6432332]
7.  Hayano, T., Sogawa, K., Ichihara, Y., Fujii-Kuriyama, Y. and Takahasi, K. Primary structure of human pepsinogen C gene. J. Biol. Chem. 263 (1988) 1382–1385. [PMID: 3335549]
[EC 3.4.23.3 created 1965 as EC 3.4.4.22, transferred 1972 to EC 3.4.23.3, modified 1986]
 
 
EC 3.4.23.4     
Accepted name: chymosin
Reaction: Broad specificity similar to that of pepsin A. Clots milk by cleavage of a single Ser-Phe105┼Met-Ala bond in κ-chain of casein
Other name(s): rennin (but this should be avoided since it leads to confusion with renin)
Comments: Neonatal gastric enzyme with high milk clotting and weak general proteolytic activity, formed from prochymosin. Found among mammals with postnatal uptake of immunoglobulins. In peptidase family A1(pepsin A family)
References:
1.  Foltmann, B. A review of prorennin and rennin. C. R. Trav. Lab. Carlsberg 35 (1966) 143–231. [PMID: 5330666]
2.  Harris, T.J.R., Lowe, P.A., Lyons, A., Thomas, P.G., Eaton, M.A.W., Millican, T.A., Patel, T.P., Bose, C.C., Carey, N.H. and Doel, M.T. Molecular cloning and nucleotide sequence of cDNA coding for calf preprochymosin. Nucleic Acids Res. 10 (1982) 2177–2187. [PMID: 6283469]
3.  Visser, S., Slangen, C.J. and van Rooijen, P.J. Peptide substrates for chymosin (rennin). Interaction sites in κ-casein-related sequences located outside the (103-108)-hexapeptide region that fits into the enzyme's active-site cleft. Biochem. J. 244 (1987) 553–558. [PMID: 3128264]
[EC 3.4.23.4 created 1961 as EC 3.4.4.3, transferred 1972 to EC 3.4.23.4, modified 1986]
 
 
EC 3.4.23.5     
Accepted name: cathepsin D
Reaction: Specificity similar to, but narrower than, that of pepsin A. Does not cleave the Gln4-His bond in B chain of insulin
Comments: Occurs intracellularly, in lysosomes. A zymogen form is known [4]. In peptidase family A1 (pepsin A family).
References:
1.  Barrett, A.J. Cathepsin D and other carboxyl proteinases. In: Barrett, A.J. (Ed.), Proteinases in Mammalian Cells and Tissues, North-Holland Publishing Co., Amsterdam, 1977, pp. 209–248.
2.  Takahashi, T. and Tang, J. Cathepsin D from porcine and bovine spleen. Methods Enzymol. 80 (1981) 565–581. [PMID: 7341918]
3.  Faust, P.L., Kornfeld, S. and Chirgwin, J.M. Cloning and sequence analysis of cDNA for human cathepsin D. Proc. Natl. Acad. Sci. USA 82 (1985) 4910–4914. [PMID: 3927292]
4.  Conner, G.E. Isolation of procathepsin D from mature cathepsin D by pepstatin affinity chromatography. Autocatalytic proteolysis of the zymogen form of the enzyme. Biochem. J. 263 (1989) 601–604. [PMID: 2512908]
[EC 3.4.23.5 created 1965 as EC 3.4.4.23, transferred 1972 to EC 3.4.23.5, modified 1986]
 
 
EC 3.4.23.6      
Transferred entry: now EC 3.4.23.30 pycnoporopepsin
[EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981, deleted 1992 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978]]
 
 
EC 3.4.23.7      
Transferred entry: Penicillium janthinellum acid proteinase. Now EC 3.4.23.20, penicillopepsin
[EC 3.4.23.7 created 1972, modified 1981, deleted 1978 [transferred to EC 3.4.23.6, deleted 1992]]
 
 
EC 3.4.23.8      
Transferred entry: yeast proteinase A. Now EC 3.4.23.25, saccharopepsin
[EC 3.4.23.8 created 1972, modified 1981, deleted 1978 [transferred to EC 3.4.23.6, deleted 1992]]
 
 
EC 3.4.23.9      
Transferred entry: Rhizopus acid proteinase. Now EC 3.4.23.21, rhizopuspepsin
[EC 3.4.23.9 created 1972, modified 1981, deleted 1978 [transferred to EC 3.4.23.6, deleted 1992]]
 
 
EC 3.4.23.10      
Transferred entry: Endothia acid proteinase. Now EC 3.4.23.22, endothiapepsin
[EC 3.4.23.10 created 1972, modified 1981, deleted 1978 [transferred to EC 3.4.23.6, deleted 1992]]
 
 
EC 3.4.23.11      
Deleted entry:  thyroid aspartic proteinase
[EC 3.4.23.11 created 1978, modified 1981, deleted 1992]
 
 
EC 3.4.23.12     
Accepted name: nepenthesin
Reaction: Similar to pepsin, but also cleaves on either side of Asp and at Lys┼Arg
Other name(s): Nepenthes aspartic proteinase; Nepenthes acid proteinase; nepenthacin; nepenthasin; aspartyl endopeptidase
Comments: From the insectivorous plants Nepenthes spp. (secretions) and Drosera peltata (ground-up leaves). Aspartic endopeptidases are probably present in many other plants, including Lotus [3] and sorghum [2]. In peptidase family A1 (pepsin A family)
References:
1.  Amagase, S., Nakayama, S. and Tsugita, A. Acid protease in Nepenthes. II. Study on the specificty of nepenthesin. J. Biochem. (Tokyo) 66 (1969) 431–439. [PMID: 5354017]
2.  Garg, G.K. and Virupaksha, T.K. Acid protease from germinated sorghum. 2. Substrate specificity with synthetic peptides and ribonuclease A. Eur. J. Biochem. 17 (1970) 4–12. [PMID: 5486576]
3.  Shinano, S. and Fukushima, K. Studies on lotus seed protease. Part III. Some physicochemical and enzymic properties. Agric. Biol. Chem. 35 (1971) 1488–1494.
4.  Amagase, S. Digestive enzymes in insectivorous plants. III. Acid proteases in the genus Nepenthes and Drosera peltata. J. Biochem. (Tokyo) 72 (1972) 73–81. [PMID: 5069751]
5.  Takahashi, K., Chang, W-J. and Ko, J-S. Specific inhibition of acid proteases from brain, kidney, skeletal muscle, and insectivorous plants by diazoacetyl-DL-norleucine methyl ester and by pepstatin. J. Biochem. (Tokyo) 76 (1974) 897–899. [PMID: 4436292]
6.  Tökés, Z.A., Woon, W.C. and Chambers, S.M. Digestive enzymes secreted by the carnivorous plant Nepenthes macferlani L. Planta 119 (1974) 39–46. [PMID: 16526095]
[EC 3.4.23.12 created 1972 as EC 3.4.99.4, transferred 1978 to EC 3.4.23.12, modified 1981]
 
 
EC 3.4.23.13      
Deleted entry: Lotus aspartic proteinase
[EC 3.4.23.13 created 1978, modified 1981, deleted 1992]
 
 
EC 3.4.23.14      
Deleted entry:  sorghum aspartic proteinase
[EC 3.4.23.14 created 1978, modified 1981, deleted 1992]
 
 
EC 3.4.23.15     
Accepted name: renin
Reaction: Cleavage of Leu┼ bond in angiotensinogen to generate angiotensin I
Other name(s): angiotensin-forming enzyme; angiotensinogenase
Comments: Formed from prorenin in plasma and kidney. In peptidase family A1 (pepsin A family).
References:
1.  Inagami, T. and Murakami, K. Pure renin. Isolation from hog kidney and characterization. J. Biol. Chem. 252 (1977) 2978–2983. [PMID: 16012]
2.  Slater, E.E. Renin. Methods Enzymol. 80 (1981) 427–442. [PMID: 7043197]
3.  Inagami, T. Structure and function of renin. J. Hypertension 2) (1989) S3–S8. [PMID: 2666611]
4.  Sielecki, A.R., Hayakawa, K., Fujinaga, M., Murphy, M.E.P., Fraser, M., Muir, A.K., Carilli, C.T., Lewicki, J.A., Baxter, J.D. and James, M.N.G. Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 Å resolution. Science 243 (1989) 1346–1351. [PMID: 2493678]
[EC 3.4.23.15 created 1961 as EC 3.4.4.15, transferred 1972 to EC 3.4.99.19, transferred 1981 to EC 3.4.23.15]
 
 
EC 3.4.23.16     
Accepted name: HIV-1 retropepsin
Reaction: Specific for a P1 residue that is hydrophobic, and P1′ variable, but often Pro
Other name(s): human immunodeficiency virus type 1 protease; gag protease; HIV aspartyl protease; HIV proteinase; retroproteinase; HIV-1 protease; HIV-2 protease
Comments: Present in human immunodeficiency virus type 1. Contributes to the maturation of the viral particle, and is a target of antiviral drugs. Active enzyme is a dimer of identical 11-kDa subunits. Similar enzymes occur in other retroviruses [1]. Type example of peptidase family A2
References:
1.  Kuo, L.C. and Shafer, J.A. (eds) Retroviral Proteases. Methods Enzymol. 241 (1994) 1–431.
2.  Dunn, B.M. Human immunodeficiency virus 1 retropepsin. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 919–928.
[EC 3.4.23.16 created 1992, modified 2000]
 
 
EC 3.4.23.17     
Accepted name: pro-opiomelanocortin converting enzyme
Reaction: Cleavage at paired basic residues in certain prohormones, either between them, or on the carboxyl side
Other name(s): prohormone converting enzyme; pro-opiomelanocortin-converting enzyme; proopiomelanocortin proteinase; PCE
Comments: A 70 kDa membrane-bound enzyme isolated from cattle pituitary secretory vesicle.
References:
1.  Loh, Y.P., Parish, D.C. and Tuteja, R. Purification and characterization of a paired basic residue-specific pro-opiomelanocortin converting enzyme from bovine pituitary intermediate lobe secretory vesicles. J. Biol. Chem. 260 (1985) 7194–7205. [PMID: 2987247]
2.  Loh, Y.P. Kinetic studies on the processing of human β-lipotropin by bovine pituitary intermediate lobe pro-opiomelanocortin-converting enzyme. J. Biol. Chem. 261 (1986) 11949–11955. [PMID: 3017955]
3.  Estivariz, F.E., Birch, N.P. and Loh, Y.P. Generation of Lys-γ3-melanotropin from pro-opiomelanocortin1-77 by a bovine intermediate lobe secretory vesicle membrane-associated aspartic protease and purified pro-opiomelanocortin converting enzyme. J. Biol. Chem. 264 (1989) 17796–17801. [PMID: 2553692]
[EC 3.4.23.17 created 1989 as EC 3.4.99.38, transferred 1992 to EC 3.4.23.17]
 
 
EC 3.4.23.18     
Accepted name: aspergillopepsin I
Reaction: Hydrolysis of proteins with broad specificity. Generally favours hydrophobic residues in P1 and P1′, but also accepts Lys in P1, which leads to activation of trypsinogen. Does not clot milk
Other name(s): Aspergillus acid protease; Aspergillus acid proteinase; Aspergillus aspartic proteinase; Aspergillus awamori acid proteinase; Aspergillus carboxyl proteinase; (see also Comments); carboxyl proteinase; Aspergillus kawachii aspartic proteinase; Aspergillus saitoi acid proteinase; pepsin-type aspartic proteinase; Aspergillus niger acid proteinase; sumizyme AP; proctase P; denapsin; denapsin XP 271; proctase
Comments: Found in a variety of Aspergillus species (imperfect fungi): Aspergillus awamori (awamorin, aspergillopepsin A: [8]), A. foetidus (aspergillopepsin F: [6]), A. fumigatus [7], A. kawachii [9], A. niger (proteinase B, proctase B: [2,4]), A. oryzae (trypsinogen kinase: [3,10]), A. saitoi (aspergillopeptidase A: [10]), and A. sojae [5,10]. In peptidase family A1 (pepsin A family). Formerly included in EC 3.4.23.6
References:
1.  Kovaleva, G.G., Shimanskaya, M.P. and Stepanov, V.M. The site of diazoacetyl inhibitor attachment to acid proteinase of Aspergillus awamori - an analog of penicillopepsin and pepsin. Biochem. Biophys. Res. Commun. 49 (1972) 1075–1082. [PMID: 4565799]
2.  Morihara, K. and Oka, T. Comparative specificity of microbial acid proteinases for synthetic peptides. III. Relationship with their trypsinogen activating ability. Arch. Biochem. Biophys. 157 (1973) 561–572. [PMID: 4593189]
3.  Davidson, R., Gertler, A. and Hofmann, T. Aspergillus oryzae acid proteinase. Purification and properties, and formation of π-chymotrypsin. Biochem. J. 147 (1975) 45–53. [PMID: 239702]
4.  Chang, W.-J., Horiuchi, S., Takahashi, K., Yamasaki, M. and Yamada, Y. The structure and function of acid proteases. VI. Effects of acid protease-specific inhibitors on the acid proteases from Aspergillus niger var. macrosporus. J. Biochem. (Tokyo) 80 (1976) 975–981. [PMID: 12156]
5.  Tanaka, N., Takeuchi, M. and Ichishima, E. Purification of an acid proteinase from Aspergillus saitoi and determination of peptide bond specificity. Biochim. Biophys. Acta 485 (1977) 406–416. [PMID: 21699]
6.  Ostoslavskaya, V.I., Kotlova, E.K., Stepanov, V.M., Rudenskaya, G.H., Baratova, L.A. and Belyanova, L.P. Aspergillopepsin F-A carboxylic proteinase from Aspergillus foetidus. Bioorg. Khim. 5 (1976) 595–603.
7.  Panneerselvam, M. and Dhar, S.C. Studies on the peptide bond specificity and the essential groups of an acid proteinase from Aspergillus fumigatus. Ital. J. Biochem. 30 (1981) 207–216. [PMID: 7024192]
8.  Ostoslavskaya, V.I., Revina, L.P., Kotlova, E.K., Surova, I.A., Levin, E.D., Timokhima, E.A. and Stepanov, V.M. The primary structure of aspergillopepsin A, aspartic proteinase from Aspergillus awamori. IV. Amino acid sequence of the enzyme. Bioorg. Khim. 12 (1986) 1030–1047.
9.  Yagi, F., Fan, J., Tadera, K. and Kobayashi, A. Purification and characterization of carboxyl proteinase from Aspergillus kawachii. Agric. Biol. Chem. 50 (1986) 1029–1033.
10.  Majima, E., Oda, K., Murao, S. and Ichishima, E. Comparative study on the specificities of several fungal aspartic and acidic proteinases towards the tetradecapeptide of a renin substrate. Agric. Biol. Chem. 52 (1988) 787–793.
[EC 3.4.23.18 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.19     
Accepted name: aspergillopepsin II
Reaction: Preferential cleavage in B chain of insulin: Asn3┼Gln, Gly13┼Ala, Tyr26┼Thr
Other name(s): proteinase A; proctase A; Aspergillus niger var. macrosporus aspartic proteinase
Comments: Isolated from Aspergillus niger var. macrosporus, distinct from proteinase B (see aspergillopepsin I) in specificity and insensitivity to pepstatin. In peptidase family A4 (scytalidopepsin B family). Formerly included in EC 3.4.23.6
References:
1.  Chang, W.-J., Horiuchi, S., Takahashi, K., Yamasaki, M. and Yamada, Y. The structure and function of acid proteases. VI. Effects of acid protease-specific inhibitors on the acid proteases from Aspergillus niger var. macrosporus. J. Biochem. (Tokyo) 80 (1976) 975–981. [PMID: 12156]
2.  Iio, K. and Yamasaki, M. Specificity of acid proteinase A from Aspergillus niger var. macrosporus towards B-chain of performic acid oxidized bovine insulin. Biochim. Biophys. Acta 429 (1976) 912–924. [PMID: 1268233]
[EC 3.4.23.19 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.20     
Accepted name: penicillopepsin
Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1′, but also cleaving Gly20┼Glu in the B chain of insulin. Clots milk, and activates trypsinogen
Other name(s): peptidase A; Penicillium janthinellum aspartic proteinase; acid protease A; Penicillium citrinum acid proteinase; Penicillium cyclopium acid proteinase; Penicillium expansum acid proteinase; Penicillium janthinellum acid proteinase; Penicillium expansum aspartic proteinase; Penicillium aspartic proteinase; Penicillium caseicolum aspartic proteinase; Penicillium roqueforti acid proteinase; Penicillium duponti aspartic proteinase; Penicillium citrinum aspartic proteinase
Comments: From the imperfect fungus Penicillium janthinellum. In peptidase family A1 (pepsin A family). Closely related enzymes have been isolated from P. roqueforti [2] and P. duponti [3].
References:
1.  Mains, G., Takahashi, M., Sodek, J. and Hofmann, T. The specificity of penicillopepsin. Can. J. Biochem. 49 (1971) 1134–1149. [PMID: 4946839]
2.  Zevaco, C., Hermier, J. and Gripon, J.-C. Le système protéolytique de Penicillium roqueforti. II - Purification et propriétés de la protéase acide. Biochimie 55 (1973) 1353–1360. [PMID: 4790849]
3.  Emi, S., Myers, D.V. and Iacobucci, G.A. Purification and properties of the thermostable acid protease of Penicillium duponti. Biochemistry 15 (1976) 842–848. [PMID: 2287]
4.  Hofmann, T. Penicillopepsin. Methods Enzymol. 45 (1976) 434–450. [PMID: 1012008]
5.  Hsu, I.-N., Delbaere, L.T.J., James, M.N.G. and Hofmann, T. Penicillopepsin from Penicillium janthinellum crystal structure at 2.8 Å and sequence homology with porcine pepsin. Nature 266 (1977) 140–144. [PMID: 323722]
[EC 3.4.23.20 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.21     
Accepted name: rhizopuspepsin
Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1′. Clots milk and activates trypsinogen. Does not cleave Gln4-His, but does cleave His10┼Leu and Val12┼Glu in B chain of insulin
Other name(s): Rhizopus aspartic proteinase; neurase; Rhizopus acid protease; Rhizopus acid proteinase
Comments: From the zygomycete fungus Rhizopus chinensis. A similar endopeptidase is found in R. niveus [2]. In peptidase family A1 (pepsin A family).
References:
1.  Tsuru, D., Hattori, A., Tsuji, H., Yamamoto, T. and Fukumoto, J. Studies on mold proteases. Part II. Substrate specificity of acid protease of Rhizopus chinensis. Agric. Biol. Chem. 33 (1969) 1419–1426.
2.  Kurono, Y., Chidimatsu, M., Horikoshi, K. and Ikeda, Y. Isolation of a protease from a Rhizopus product. Agric. Biol. Chem. 35 (1971) 1668–1675.
3.  Ohtsuru, M., Tang, J. and Delaney, R. Purification and characterization of rhizopuspesin isozymes from a liquid culture of Rhizopus chinensis. Int. J. Biochem. 14 (1982) 925–932. [PMID: 6751894]
4.  Suguna, K., Padlan, E.A., Smith, C.W., Carlson, W.D. and Davies, D.R. Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action. Proc. Natl. Acad. Sci. USA 84 (1987) 7009–7013. [PMID: 3313384]
[EC 3.4.23.21 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.22     
Accepted name: endothiapepsin
Reaction: Hydrolysis of proteins with specificity similar to that of pepsin A; prefers hydrophobic residues at P1 and P1′, but does not cleave Ala14-Leu in the B chain of insulin or Z-Glu-Tyr. Clots milk
Other name(s): Endothia aspartic proteinase; Endothia acid proteinase; Endothia parasitica acid proteinase; Endothia parasitica aspartic proteinase
Comments: From the ascomycete Endothia parasitica. In peptidase family A1 (pepsin A family).
References:
1.  Whitaker, J.R. Protease of Endothia parasitica. Methods Enzymol. 19 (1970) 436–445.
2.  Williams, D.C., Whitaker, J.R. and Caldwell, P.V. Hydrolysis of peptide bonds of the oxidized B-chain of insulin by Endothia parasitica protease. Arch. Biochem. Biophys. 149 (1972) 52–61. [PMID: 4552802]
3.  Barkholt, V. Amino acid sequence of endothiapepsin. Complete primary structure of the aspartic protease from Endothia parasitica. Eur. J. Biochem. 167 (1987) 327–338. [PMID: 3305016]
4.  Cooper, J., Foundling, S., Hemmings, A., Blundell, T., Jones, D.M., Hallett, A. and Szelke, M. The structure of a synthetic pepsin inhibitor complexed with endothiapepsin. Eur. J. Biochem. 169 (1987) 215–221. [PMID: 3119339]
[EC 3.4.23.22 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.23     
Accepted name: mucorpepsin
Reaction: Hydrolysis of proteins, favouring hydrophobic residues at P1 and P1′. Clots milk. Does not accept Lys at P1, and hence does not activate trypsinogen
Other name(s): Mucor rennin; Mucor aspartic proteinase; Mucor acid proteinase; Mucor acid protease; Mucor miehei aspartic proteinase; Mucor miehei aspartic protease; Mucor aspartic proteinase; Mucor pusillus emporase; Fromase 100; Mucor pusillus rennin; Fromase 46TL; Mucor miehei rennin
Comments: Isolated from the zygomycete fungi Mucor pusillus and M. miehei. The two species variants show 83% sequence identity and are immunologically crossreactive. In peptidase family A1 (pepsin A family). Formerly included in EC 3.4.23.6
References:
1.  Arima, K., Yu, J. and Iwasaki, S. Milk-clotting enzyme from Mucor pusillus var. lindt. Methods Enzymol. 19 (1970) 446–459.
2.  Ottesen, M. and Rickert, W. The acid protease of Mucor miehei. Methods Enzymol. 19 (1970) 459–460.
3.  Sternberg, M. Bond specificity, active site and milk cloting mechanism of the Mucor miehei protease. Biochim. Biophys. Acta 285 (1972) 383–392. [PMID: 4573298]
4.  Oka, T., Ishino, K., Tsuzuki, H., Morihara, K. and Arima, K. On the specificity of a rennin-like enzyme from Mucor pusillus. Agric. Biol. Chem. 37 (1973) 1177–1184.
5.  Baudy, M., Foundling, S., Pavlik, M., Blundell, T. and Kostka, V. Protein chemical characterization of Mucor pusillus aspartic proteinase. Amino acid sequence homology with the other aspartic proteinases, disulfide bond arrangement and site of carbohydrate attachment. FEBS Lett. 235 (1988) 271–274. [PMID: 3042459]
[EC 3.4.23.23 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.24     
Accepted name: candidapepsin
Reaction: Preferential cleavage at the carboxyl of hydrophobic amino acids, but fails to cleave Leu15-Tyr, Tyr16-Leu and Phe24-Phe of insulin B chain. Activates trypsinogen, and degrades keratin
Other name(s): Candida albicans aspartic proteinase; Candida albicans carboxyl proteinase; Candida albicans secretory acid proteinase; Candida olea acid proteinase; Candida aspartic proteinase; Candida olea aspartic proteinase; Candida albicans aspartic proteinase
Comments: This endopeptidase from the imperfect yeast Candida albicans is inhibited by pepstatin, but not by methyl 2-diazoacetamidohexanoate or 1,2-epoxy-3-(p-nitrophenoxy)propane. In peptidase family A1 (pepsin A family). Formerly included in EC 3.4.23.6
References:
1.  Remold, H., Fasold, H. and Staib, F. Purification and characterization of a proteolytic enzyme from Candida albicans. Biochim. Biophys. Acta 167 (1968) 399–406. [PMID: 5729955]
2.  Rüchel, R. Properties of a purified proteinase from the yeast Candida albicans. Biochim. Biophys. Acta 659 (1981) 99–113. [PMID: 7018586]
3.  Negi, M., Tsuboi, R., Matsui, T. and Ogawa, H. Isolation and characterization of proteinase from Candida albicans: substrate specificity. J. Invest. Dermatol. 83 (1984) 32–36. [PMID: 6203988]
4.  Lott, T.J., Page, L.S., Boiron, P., Benson, J. and Reiss, E. Nucleotide sequence of the Candida albicans aspartyl proteinase gene. Nucleic Acids Res. 17 (1989) 1779. [PMID: 2646602]
[EC 3.4.23.24 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.25     
Accepted name: saccharopepsin
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds. Cleaves -Leu-Leu┼Val-Tyr bond in a synthetic substrate. Does not act on esters of Tyr or Arg
Other name(s): yeast endopeptidase A; Saccharomyces aspartic proteinase; aspartic proteinase yscA; proteinase A; proteinase yscA; yeast proteinase A; Saccharomyces cerevisiae aspartic proteinase A; yeast proteinase A; PRA
Comments: Located in the vacuole of the baker's yeast (Saccharomyces cerevisiae) cell. In peptidase family A1 (pepsin A family).
References:
1.  Hata, T., Hayashi, R. and Dot, E. Purification of yeast proteinases. Part III. Isolation and physicochemical properties of yeast proteinase A and C. Agric. Biol. Chem. 31 (1967) 357–367.
2.  Meussdoerffer, F., Tortora, P. and Holzer, H. Purification and properties of proteinase A from yeast. J. Biol. Chem. 255 (1980) 12087–12093. [PMID: 7002931]
3.  Ammerer, G., Hunter, C.P., Rothman, J.H., Saari, G.C., Valls, L.A. and Stevens, T.H. PEP4 gene of Saccharomyces cerevisiae encodes proteinase A, a vacuolar enzyme required for processing of vacuolar precursors. Mol. Cell. Biol. 6 (1987) 2490–2499. [PMID: 3023936]
[EC 3.4.23.25 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.26     
Accepted name: rhodotorulapepsin
Reaction: Specificity similar to that of pepsin A. Cleaves Z-Lys┼Ala-Ala-Ala and activates trypsinogen
Other name(s): Rhodotorula aspartic proteinase; Cladosporium acid protease; Cladosporium acid proteinase; Paecilomyces proteinase; Cladosporium aspartic proteinase; Paecilomyces proteinase; Rhodotorula glutinis aspartic proteinase; Rhodotorula glutinis acid proteinase; Rhodotorula glutinis aspartic proteinase II; Rhodotorula acid proteinase
Comments: From the imperfect yeast Rhodotorula glutinis. Somewhat similar enzymes have been isolated from the imperfect yeast-like organism Cladosporium sp. [4,6] and the imperfect fungus Paecilomyces varioti [1,2].
References:
1.  Sawada, J. Studies on the acid-protease of Paecilomyces varioti Bainier TPR-220. Part I. Crystallization of the acid-protease of Paecilomyces varioti Bainier TPR-220. Agric. Biol. Chem. 27 (1963) 677–683.
2.  Sawada, J. The acid-protease of Paecilomyces varioti. III. The specificity of the crystalline acid-protease on synthetic substrates. Agric. Biol. Chem. 28 (1964) 869–875.
3.  Kamada, M., Oda, K. and Murao, S. The purification of the extracellular acid protease of Rhodotorula glutinis K-24 and its general properties. Agric. Biol. Chem. 36 (1972) 1095–1101.
4.  Murao, S., Funakoshi, S. and Oda, K. Purification, crystallization and some enzymatic properties of acid protease of Cladosporium sp. No. 45-2. Agric. Biol. Chem. 36 (1972) 1327–1333.
5.  Oda, K., Kamada, M. and Murao, S. Some physicochemical properties and substrate specificity of acid protease of Rhodotorula glutinis K-24. Agric. Biol. Chem. 36 (1972) 1103–1108.
6.  Oda, K., Funakoshi, S. and Murao, S. Some physicochemical properties and substrate specificity of acid protease isolated from Cladosporium sp. No. 45-2. Agric. Biol. Chem. 37 (1973) 1723–1729.
7.  Takahashi, K. and Chang, W.-J. The structure and function of acid proteases. V. Comparative studies on the specific inhibition of acid proteases by diazoacetyl-DL-norleucine methyl ester, 1,2-epoxy-3-(p-nitrophenoxy)propane and pepstatin. J. Biochem. (Tokyo) 80 (1976) 497–506. [PMID: 10290]
8.  Majima, E., Oda, K., Murao, S. and Ichishima, E. Comparative study on the specificities of several fungal aspartic and acidic proteinases towards the tetradecapeptide of a renin substrate. Agric. Biol. Chem. 52 (1988) 787–793.
[EC 3.4.23.26 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.27      
Transferred entry: physaropepsin. Now EC 3.4.21.103, physarolisin
[EC 3.4.23.27 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992), deleted 2003]
 
 
EC 3.4.23.28     
Accepted name: acrocylindropepsin
Reaction: Preference for hydrophobic residues at P1 and P1′. Action on the B chain of insulin is generally similar to that of pepsin A, but it also cleaves Leu6┼Cys(SO3H), Glu21┼Arg and Asn3┼Gln, although not Gln4-His
Other name(s): Acrocylindrium proteinase; Acrocylindrium acid proteinase
Comments: From the imperfect fungus Acrocylindrium sp. Has a very low pH optimum on casein of 2.0. In peptidase family A1 (pepsin A family).
References:
1.  Uchino, F., Kurono, Y. and Doi, S. Purification and some properties of crystalline acid protease from Acrocylindrium sp. Agric. Biol. Chem. 31 (1967) 428–434.
2.  Ichihara, S. and Uchino, F. The specificity of acid proteinase from Acrocylindrium. Agric. Biol. Chem. 39 (1975) 423–428.
3.  Takahashi, K. and Chang, W.-J. The structure and function of acid proteases. V. Comparative studies on the specific inhibition of acid proteases by diazoacetyl-DL-norleucine methyl ester, 1,2-epoxy-3-(p-nitrophenoxy)propane and pepstatin. J. Biochem. (Tokyo) 80 (1976) 497–506. [PMID: 10290]
[EC 3.4.23.28 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.29     
Accepted name: polyporopepsin
Reaction: Milk clotting activity, broad specificity, but fails to cleave Leu15-Tyr or Tyr16-Leu of insulin B chain
Other name(s): Polyporus aspartic proteinase; Irpex lacteus aspartic proteinase; Irpex lacteus carboxyl proteinase B
Comments: From the basidiomycete Polyporus tulipiferae (formerly Irpex lacteus). In peptidase family A1 (pepsin A family)
References:
1.  Kobayashi, H., Kusakabe, I. and Murakami, K. Substrate specificity of a carboxyl proteinase from Irpex lacteus. Agric. Biol. Chem. 47 (1983) 1921–1923.
2.  Kobayashi, H., Sekibata, S., Shibuya, H., Yoshida, S., Kusakabe, I. and Murakami, K. Cloning and sequence analysis of cDNA for Irpex lacteus aspartic proteinase. Agric. Biol. Chem. 53 (1989) 1927–1933.
[EC 3.4.23.29 created 1992]
 
 
EC 3.4.23.30     
Accepted name: pycnoporopepsin
Reaction: Similar to pepsin A, but narrower, cleaving only three bonds in the B chain of insulin: Ala14┼Leu, Tyr16┼Leu, and Phe24┼Phe
Other name(s): proteinase Ia; Pycnoporus coccineus aspartic proteinase; Trametes acid proteinase
Comments: From the basidiomycete Pycnoporus sanguineus, formerly known as P. coccineus and Trametes sanguinea. Formerly included in EC 3.4.23.6
References:
1.  Tomoda, K. and Shimazono, H. Acid protease produced by Trametes sanguinea a wood-destroying fungus. Part I. Purification and crystallization of the enzyme. Agric. Biol. Chem. 28 (1964) 770–773.
2.  Tsuru, D., Hattori, A., Tsuji, H., Yamamoto, T. and Fukumoto, J. Studies on mold proteases. Part II. Substrate specificity of acid protease of Rhizopus chinensis. Agric. Biol. Chem. 33 (1969) 1419–1426.
3.  Ichishima, E., Kumagai, H. and Tomoda, K. Substrate specificity of carboxyl proteinase from Pycnoporus coccineus, a wood-deteriorating fungus. Curr. Microbiol. 3 (1980) 333–337.
[EC 3.4.23.30 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.31     
Accepted name: scytalidopepsin A
Reaction: Hydrolysis of proteins with specificity similar to that of pepsin A, but also cleaves Cys(SO3H)7┼Gly and Leu17┼Val in the B chain of insulin
Other name(s): Scytalidium aspartic proteinase A; Scytalidium lignicolum aspartic proteinase; Scytalidium lignicolum aspartic proteinase A-2; Scytalidium lignicolum aspartic proteinase A-I; Scytalidium lignicolum aspartic proteinase C; Scytalidium lignicolum carboxyl proteinase; Scytalidium lignicolum acid proteinase
Comments: Isolated from the imperfect fungus Scytalidium lignicolum. Not inhibited by pepstatin-Ac, methyl 2-diazoacetamidohexanoate or 1,2-epoxy-3-(p-nitrophenyl)propane. A related enzyme from the same organism, proteinase C, is also insensitive to these inhibitors and has Mr = 406,000 [3]
References:
1.  Oda, K. and Murao, S. Purification and some enzymatic properties of acid protease A and B of Scytalidium lignicolum ATCC 24568. Agric. Biol. Chem. 38 (1974) 2435–2444.
2.  Oda, K. and Murao, S. Action of Scytalidium lignicolum acid proteases on insulin B-chain. Agric. Biol. Chem. 40 (1976) 1221–1225.
3.  Oda, K., Torishima, H. and Murao, S. Purification and characterization of acid proteinase C of Scytalidium lignicolum ATCC 24568. Agric. Biol. Chem. 50 (1986) 651–658.
[EC 3.4.23.31 created 1992]
 
 
EC 3.4.23.32     
Accepted name: scytalidopepsin B
Reaction: Hydrolysis of proteins with broad specificity, cleaving Phe24┼Phe, but not Leu15-Tyr and Phe25-Tyr in the B chain of insulin
Other name(s): Scytalidium aspartic proteinase B; Ganoderma lucidum carboxyl proteinase; Ganoderma lucidum aspartic proteinase; Scytalidium lignicolum aspartic proteinase B; SLB
Comments: A second endopeptidase from Scytalidium lignicolum (see scytalidopepsin A) that is insensitive to pepstatin and methyl 2-diazoacetamidohexanoate. 1,2-Epoxy-3-(p-nitrophenoxy)propane reacts with Glu53, which replaces one of the aspartic residues at the active centre. One of the smallest aspartic endopeptidases active as the monomer, with Mr 22,000. Similarly inhibitor-resistant endopeptidases are found in the basidiomycetes Lentinus edodes [1] and Ganoderma lucidum [3], and in Polyporus tulipiferae [4], a second endopeptidase distinct from polyporopepsin, but these are of typical aspartic endopeptidase size, Mr about 36,000. Type example of peptidase family G1.
References:
1.  Terashita, T., Oda, K., Kono, M. and Murao, S. Streptomyces pepsin inhibitor-insensitive carboxyl proteinase from Lentinus edodes. Agric. Biol. Chem. 45 (1981) 1937–1943.
2.  Maita, T., Nagata, S., Matsuda, G., Maruta, S., Oda, K., Murao, S. and Tsuru, D. Complete amino acid sequence of Scytalidium lignicolum acid protease B. J. Biochem. (Tokyo) 95 (1984) 465–473. [PMID: 6370989]
3.  Terashita, T., Oda, K., Kono, M. and Murao, S. Streptomyces pepsin inhibitor-insensitive carboxyl proteinase from Ganoderma lucidum. Agric. Biol. Chem. 48 (1984) 1029–1035.
4.  Kobayashi, H., Kusakabe, I. and Murakami, K. Purification and characterization of a pepstatin-insensitive carboxyl proteinase from Polyporus tulipiferae (Irpex lacteus). Agric. Biol. Chem. 49 (1985) 2393–2397.
5.  Tsuru, D., Shimada, S., Maruta, S., Yoshimoto, T., Oda, K., Murao, S., Miyata, T. and Iwanaga, S. Isolation and amino acid sequence of a peptide containing an epoxide-reactive residue from the thermolysin-digest of Scytalidium lignicolum acid protease B. J. Biochem. (Tokyo) 99 (1986) 1537–1539. [PMID: 3519605]
[EC 3.4.23.32 created 1992]
 
 
EC 3.4.23.33      
Transferred entry: xanthomonapepsin. Now EC 3.4.21.101, xanthomonalisin
[EC 3.4.23.33 created 1992, deleted 2001]
 
 
EC 3.4.23.34     
Accepted name: cathepsin E
Reaction: Similar to cathepsin D, but slightly broader specificity
Other name(s): slow-moving proteinase; erythrocyte membrane aspartic proteinase; SMP; erythrocyte membrane aspartic proteinase; EMAP; non-pepsin proteinase; cathepsin D-like acid proteinase; cathepsin E-like acid proteinase; cathepsin D-type proteinase
Comments: Found in stomach, spleen, erythrocyte membrane; not lysosomal. Pro-cathepsin E is an 86 kDa disulfide-linked dimer; activation or reduction produces monomer. In peptidase family A1 (pepsin A family)
References:
1.  Lapresle, C., Puizdar, V., Porchon-Bertolotto, C., Joukoff, E. and Turk, V. Structural differences between rabbit cathepsin E and cathepsin D. Biol. Chem. Hoppe-Seyler 367 (1986) 523–526. [PMID: 3741628]
2.  Yonezawa, S., Fujii, K., Maejima, Y., Tamoto, K., Mori, Y. and Muto, N. Further studies on rat cathepsin E: subcellular localization and existence of the active subunit form. Arch. Biochem. Biophys. 267 (1988) 176–183. [PMID: 3058036]
3.  Jupp, R.A., Richards, A.D., Kay, J., Dunn, B.M., Wyckoff, J.B., Samloff, I.M. and Yamamoto, K. Identification of the aspartic proteinases from human erythrocyte membranes and gastric mucosa (slow-moving proteinase) as catalytically equivalent to cathepsin E. Biochem. J. 254 (1988) 895–898. [PMID: 3058118]
4.  Azuma, T., Pals, G., Mohandas, T.K., Couvreur, J.M. and Taggart, R.T. Human gastric cathepsin E. Predicted sequence, localization to chromosome 1, and sequence homology with other aspartic proteinases. J. Biol. Chem. 264 (1989) 16748–16753. [PMID: 2674141]
[EC 3.4.23.34 created 1992]
 
 
EC 3.4.23.35     
Accepted name: barrierpepsin
Reaction: Selective cleavage of -Leu6┼Lys- bond in the pheromone α-mating factor
Other name(s): barrier proteinase; Bar proteinase
Comments: A secreted endopeptidase known from baker's yeast (Saccharomyces cerevisiae). In peptidase family A1 (pepsin A family)
References:
1.  Mackay, V.L., Welch, S.K., Insley, M.Y., Manney, T.R., Holly, J., Saari, G.C. and Parker, M.L. The Saccharomyces cerevisiae BAR1 gene encodes an exported protein with homology to pepsin. Proc. Natl. Acad. Sci. USA 85 (1988) 55–59. [PMID: 3124102]
2.  Mackay, V.L., Armstrong, J., Yip, C., Welch, S., Walker, K., Osborn, S., Sheppard, P. and Forstrom, J. Characterization of the bar proteinase, an extracellular enzyme from the yeast Saccharomyces cerevisiae. Adv. Exp. Med. Biol. 306 (1991) 161–172. [PMID: 1812704]
[EC 3.4.23.35 created 1993]
 
 
EC 3.4.23.36     
Accepted name: signal peptidase II
Reaction: Release of signal peptides from bacterial membrane prolipoproteins including murein prolipoprotein. Hydrolyses -Xaa-Yaa-Zaa┼(S,diacylglyceryl)Cys-, in which Xaa is hydrophobic (preferably Leu), and Yaa (Ala or Ser) and Zaa (Gly or Ala) have small, neutral sidechains
Other name(s): premurein-leader peptidase; prolipoprotein signal peptidase; leader peptidase II; premurein leader proteinase; leader peptidase II
Comments: An 18-kDa enzyme present in bacterial inner membranes. Inhibited by pepstatin and the antibiotic globomycin. Type example of peptidase family A8.
References:
1.  Dev, I.K. and Ray, P.H. Signal peptidases and signal peptide hydrolases. J. Bioenerg. Biomembr. 22 (1990) 271–290. [PMID: 2202720]
2.  Zhao, X.-J. and Wu, H.C. Nucleotide sequence of the Staphylococcus aureus signal peptidase II (lsp) gene. FEBS Lett. 299 (1992) 80–84. [PMID: 1544479]
3.  Sankaran, K. and Wu, H.C. Bacterial prolipoprotein signal peptidase. Methods Enzymol. 248 (1995) 169–180. [PMID: 7674920]
[EC 3.4.23.36 created 1984 as EC 3.4.99.35, transferred 1995 to EC 3.4.23.36]
 
 
EC 3.4.23.37      
Transferred entry: pseudomonapepsin. Now EC 3.4.21.100, pseudomonalisin
[EC 3.4.23.37 created 1995]
 
 
EC 3.4.23.38     
Accepted name: plasmepsin I
Reaction: Hydrolysis of the -Phe33┼Leu- bond in the α-chain of hemoglobin, leading to denaturation of the molecule
Other name(s): aspartic hemoglobinase I; PFAPG; malaria aspartic hemoglobinase
Comments: Known from the malaria organism, Plasmodium. About 37 kDa. In peptidase family A1 (pepsin A family), closest to cathepsin D and renin in structure. Inhibited by pepstatin. Formerly included in EC 3.4.23.6
References:
1.  Goldberg, D.E., Slater, A.F.G., Beavis, R., Chait, B., Cerami, A. and Henderson, G.B. Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease. J. Exp. Med. 173 (1991) 961–969. [PMID: 2007860]
2.  Francis, S.E., Gluzman, I.Y., Oksman, A., Knickerbocker, A., Mueller, R., Bryant, M.L., Sherman, D.R., Russell, D.G. and Goldberg, D.E. Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. EMBO J. 13 (1994) 306–317. [PMID: 8313875]
3.  Gluzman, I.Y., Francis, S.E., Oksman, A., Smith, C.E., Duffin, K.L. and Goldberg, D.E. Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. J. Clin. Invest. 93 (1994) 1602–1608. [PMID: 8163662]
[EC 3.4.23.38 created 1995]
 
 
EC 3.4.23.39     
Accepted name: plasmepsin II
Reaction: Hydrolysis of the bonds linking certain hydrophobic residues in hemoglobin or globin. Also cleaves the small molecule substrates such as Ala-Leu-Glu-Arg-Thr-Phe┼Phe(NO2)-Ser-Phe-Pro-Thr [3]
Other name(s): aspartic hemoglobinase II; PFAPD
Comments: Known from the malaria organism, Plasmodium. About 37 kDa. In peptidase family A1 (pepsin A family), and is 73% identical in sequence to plasmepsin I. Inhibited by pepstatin. Formerly included in EC 3.4.23.6
References:
1.  Dame, J.B., Reddy, G.R., Yowell, C.A., Dunn, B.M., Kay, J. and Berry, C. Sequence, expression and modelled structure of an aspartic proteinase from the human malaria parasite Plasmodium falciparum. Mol. Biochem. Parasitol. 64 (1994) 177–190. [PMID: 7935597]
2.  Gluzman, I.Y., Francis, S.E., Oksman, A., Smith, C.E., Duffin, K.L. and Goldberg, D.E. Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. J. Clin. Invest. 93 (1994) 1602–1608. [PMID: 8163662]
3.  Hill, J., Tyas, L., Phylip, L.H., Kay, J., Dunn, B.M. and Berry, C. High level expression and characterisation of plasmepsin II, an aspartic proteinase from Plasmodium falciparum. FEBS Lett. 352 (1994) 155–158. [PMID: 7925966]
[EC 3.4.23.39 created 1995]
 
 
EC 3.4.23.40     
Accepted name: phytepsin
Reaction: Prefers hydrophobic residues Phe, Val, Ile, Leu, and Ala at P1 and P1′, but also cleaves -Phe┼Asp- and -Asp┼Asp- bonds in 2S albumin from plant seeds
Comments: Known particularly from barley grain, but present in other plants also. In peptidase family A1 (pepsin A family), but structurally distinct in containing an internal region of about 100 amino acids not generally present in the family
References:
1.  Runeberg-Roos, P., Törmäkangas, K. and Östman, A. Primary structure of a barley-grain aspartic proteinase. A plant aspartic proteinase resembling mammalian cathepsin D. Eur. J. Biochem. 202 (1991) 1021–1027. [PMID: 1722454]
2.  Kervinen, J., Sarkkinen, P., Kalkkinen, N., Mikola, L. and Saarma, M. Hydrolytic specificity of the barley grain aspartic proteinase. Phytochemistry 32 (1993) 799–803. [PMID: 7763475]
3.  Asakura, T., Watanabe, H., Abe, K. and Arai, S. Rice aspartic proteinase, oryzasin, expressed during seed ripening and germination, has a gene organization distinct from those of animal and microbial aspartic proteinases. Eur. J. Biochem. 232 (1995) 77–83. [PMID: 7556174]
4.  Kervinen, J., Törmäkangas, K., Runeberg-Roos, P., Guruprasad, K., Blundell, T. and Teeri, T.H. Structure and possible function of aspartic proteinases in barley and other plants. Adv. Exp. Med. Biol. 362 (1995) 241–254. [PMID: 8540324]
[EC 3.4.23.40 created 1997]
 
 
EC 3.4.23.41     
Accepted name: yapsin 1
Reaction: Hydrolyses various precursor proteins with Arg or Lys in P1, and commonly Arg or Lys also in P2. The P3 amino acid is usually non-polar, but otherwise additional basic amino acids are favourable in both non-prime and prime positions
Other name(s): yeast aspartic protease 3; Yap3 gene product (Saccharomyces cerevisiae)
Comments: In peptidase family A1 of pepsin, and weakly inhibited by pepstatin. Can partially substitute for kexin in a deficient strain of yeast. The homologous product of the Mkc7 gene (Saccharomyces cerevisiae) has similar catalytic activity and has been termed yapsin 2 [2]
References:
1.  Cawley, N.X., Chen, H.C., Beinfeld, M.C. and Loh, Y.P. Specificity and kinetic studies on the cleavage of various prohormone mono- and paired-basic residue sites by yeast aspartic protease 3. J. Biol. Chem. 271 (1996) 4168–4176. [PMID: 8626758]
2.  Fuller, R.S. Yapsin 2. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 908–909.
3.  Olsen, V., Guruprasad, K., Cawley, N.X., Chen, H.C., Blundell, T.L. and Loh, Y.P. Cleavage efficiency of the novel aspartic protease yapsin 1 (Yap3p) enhanced for substrates with arginine residues flanking the P1 site: correlation with electronegative active-site pockets predicted by molecular modeling. Biochemistry 37 (1998) 2768–2777. [PMID: 9485427]
[EC 3.4.23.41 created 2000]
 
 
EC 3.4.23.42     
Accepted name: thermopsin
Reaction: Similar in specificity to pepsin A preferring bulky hydrophobic amino acids in P1 and P1′
Comments: From the thermophilic archaeon Sulfolobus acidocaldarius. Maximally active at pH 2 and 90 °C. Weakly inhibited by pepstatin but shows no sequence similarity to pepsin. Type example of peptidase family A5.
References:
1.  Lin, X. and Tang, J. Thermopsin. Methods Enzymol. 248 (1995) 156–168. [PMID: 7674919]
[EC 3.4.23.42 created 1992 as EC 3.4.99.43, transferred 2000 to EC 3.4.23.42]
 
 
EC 3.4.23.43     
Accepted name: prepilin peptidase
Reaction: Typically cleaves a -Gly┼Phe- bond to release an N-terminal, basic peptide of 5-8 residues from type IV prepilin, and then N-methylates the new N-terminal amino group, the methyl donor being S-adenosyl-L-methionine
Comments: Many species of bacteria carry pili on their cell surfaces. These are virulence determinants in pathogenic strains, and are assembled biosynthetically from type IV prepilin subunits. Before assembly, the prepilin molecules require proteolytic processing, which is done by the prepilin peptidase. Prepilin peptidase and its homologues play a central role not only in type IV pilus biogenesis but also in transport of macromolecules across cell membranes. Although both peptide-bond hydrolysis and N-methylation are catalysed by the same molecule, the methylation can be inhibited without affecting peptidase activity, and it is believed that the enzyme has two separate catalytic sites. Type example of peptidase family A24.
References:
1.  Lory, S. and Strom, M.S. Structure-function relationship of type-IV prepilin peptidase of Pseudomonas aeruginosa - A review. Gene 192 (1997) 117–121. [PMID: 9224881]
2.  LaPointe, C.F. and Taylor, R.K. The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases. J. Biol. Chem. 275 (2000) 1502–1510. [PMID: 10625704]
[EC 3.4.23.43 created 2001]
 
 
EC 3.4.23.44     
Accepted name: nodavirus endopeptidase
Reaction: Hydrolysis of an asparaginyl bond involved in the maturation of the structural protein of the virus, typically -Asn┼Ala- or -Asn┼Phe-
Other name(s): Black Beetle virus endopeptidase; Flock House virus endopeptidase
Comments: A single aspartic residue is critical for activity, and inhibition by EDTA indicates that a metal ion is also important. The enzyme is known from several nodaviruses that are pathogens of insects. Type example of peptidase family A6, and structurally related to the tetravirus endopeptidase in family A21, although in that family, the catalytic residue is thought to be Glu.
References:
1.  Zlotnick, A., Reddy, V.S., Dasgupta, R., Schneemann, A., Ray, W.J., Jr., Rueckert, R.R. and Johnson, J.E. Capsid assembly in a family of animal viruses primes an autoproteolytic maturation that depends on a single aspartic acid residue. J. Biol. Chem. 269 (1994) 13680–13684. [PMID: 8175803]
2.  Johnson, J.E. and Schneemann, A. Nodavirus endopeptidase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 964–967.
[EC 3.4.23.44 created 2001]
 
 
EC 3.4.23.45     
Accepted name: memapsin 1
Reaction: Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu┼Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein
Other name(s): β-secretase; β-site Alzheimer's amyloid precursor protein cleaving enzyme 2 (BACE2); ASP1; Down region aspartic protease
Comments: Can cleave β-amyloid precursor protein to form the amyloidogenic β-peptide that is implicated in the pathology of Alzheimer's disease, but is not significantly expressed in human brain. In peptidase family A1, but is atypical in containing a C-terminal membrane-spanning domain.
References:
1.  Turner, R.T., Loy, J.A., Nguyen, C., Devasamudram, T., Ghosh, A.K., Koelsch, G. and Tang, J. Specificity of memapsin 1 and its implications on the design of memapsin 2 (β-secretase) inhibitor selectivity. Biochemistry 41 (2002) 8742–8746. [PMID: 12093293]
[EC 3.4.23.45 created 2003]
 
 
EC 3.4.23.46     
Accepted name: memapsin 2
Reaction: Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu┼Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein
Other name(s): β-secretase; β-site Alzheimer's amyloid precursor protein cleaving enzyme 1 (BACE1)
Comments: Suggested to be the major "β-secretase" responsible for the cleavage of the β-amyloid precursor protein to form the amyloidogenic β-peptide that is implicated in the pathology of Alzheimer's disease. In peptidase family A1 but is atypical in containing a C-terminal membrane-spanning domain.
References:
1.  Turner, R.T., III, K oelsch, G., Hong, L., Castenheira, P., Ghosh, A. and Tang, J. Subsite specificity of memapsin 2 (β-secretase): implications for inhibitor design. Biochemistry 40 (2001) 10001–10006. [PMID: 11513577]
2.  Hong, L., Turner, R.T., Koelsch, G., Shin, D., Ghosh, A.K. and Tang, J. Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3. Biochemistry 41 (2002) 10963–10967. [PMID: 12206667]
[EC 3.4.23.46 created 2003]
 
 
EC 3.4.23.47     
Accepted name: HIV-2 retropepsin
Reaction: Endopeptidase for which the P1 residue is preferably hydrophobic
Comments: In peptidase family A2. Responsible for the post-translational processing of the human immunodeficiency virus polyprotein.
References:
1.  Tözsér, J., Bláha, I., Copeland, T.D., Wondrak, E.M. and Oroszlan, S. Comparison of the HIV-1 and HIV-2 proteinases using oligopeptide substrates representing cleavage sites in Gag and Gag-Pol polyproteins. FEBS Lett. 281 (1991) 77–80. [PMID: 2015912]
2.  Chen, Z., Li, Y., Chen, E., Hall, D., Darke, P., Culberson, C., Shafer, J.A. and Kuo, L.A. Crystal structure at 1.9-Å resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. J. Biol. Chem. 269 (1994) 26344–26348. [PMID: 7929352]
[EC 3.4.23.47 created 2003]
 
 
EC 3.4.23.48     
Accepted name: plasminogen activator Pla
Reaction: Converts human Glu-plasminogen to plasmin by cleaving the Arg560┼Val peptide bond that is also hydrolysed by the mammalian u-plasminogen activator and t-plasminogen activator. Also cleaves arginyl bonds in other proteins
Comments: In peptidase family A26. From the bacterium Yersinia pestis that causes plague.
References:
1.  Kukkonen, M., Lähteenmäki, K., Suomalainen, M., Kalkkinen, N., Emödy, L., Laang, H. and Korhonen, T.K. Protein regions important for plasminogen activation and inactivation of α2-antiplasmin in the surface protease Pla of Yersinia pestis. Mol. Microbiol. 40 (2001) 1097–1111. [PMID: 11401715]
[EC 3.4.23.48 created 2003]
 
 
EC 3.4.23.49     
Accepted name: omptin
Reaction: Has a virtual requirement for Arg in the P1 position and a slightly less stringent preference for this residue in the P1′ position, which can also contain Lys, Gly or Val.
Other name(s): protease VII; protease A; gene ompT proteins; ompT protease; protein a; Pla; OmpT
Comments: A product of the ompT gene of Escherichia coli, and associated with the outer membrane. Omptin shows a preference for cleavage between consecutive basic amino acids, but is capable of cleavage when P1′ is a non-basic residue [5,7]. Belongs in peptidase family A26.
References:
1.  Grodberg, J., Lundrigan, M.D., Toledo, D.L., Mangel, W.F. and Dunn, J.J. Complete nucleotide sequence and deduced amino acid sequence of the ompT gene of Escherichia coli K-12. Nucleic Acids Res. 16 (1988) 1209. [PMID: 3278297]
2.  Sugimura, K. and Nishihara, T. Purification, characterization, and primary structure of Escherichia coli protease VII with specificity for paired basic residues: identity of protease VII and ompT. J. Bacteriol. 170 (1988) 5625–5632. [PMID: 3056908]
3.  Hanke, C., Hess, J., Schumacher, G. and Goebel, W. Processing by OmpT of fusion proteins carrying the HlyA transport signal during secretion by the Escherichia coli hemolysin transport system. Mol. Gen. Genet. 233 (1992) 42–48. [PMID: 1603076]
4.  Dekker, N. Omptin. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 212–216.
5.  Vandeputte-Rutten, L., Kramer, R.A., Kroon, J., Dekker, N., Egmond, M.R. and Gros, P. Crystal structure of the outer membrane protease OmpT from Escherichia coli suggests a novel catalytic site. EMBO J. 20 (2001) 5033–5039. [PMID: 11566868]
6.  Kramer, R.A., Vandeputte-Rutten, L., de Roon, G.J., Gros, P., Dekker, N. and Egmond, M.R. Identification of essential acidic residues of outer membrane protease OmpT supports a novel active site. FEBS Lett. 505 (2001) 426–430. [PMID: 11576541]
7.  McCarter, J.D., Stephens, D., Shoemaker, K., Rosenberg, S., Kirsch, J.F. and Georgiou, G. Substrate specificity of the Escherichia coli outer membrane protease OmpT. J. Bacteriol. 186 (2004) 5919–5925. [PMID: 15317797]
[EC 3.4.23.49 created 1993 as EC 3.4.21.87, transferred 2006 to EC 3.4.23.49]
 
 
EC 3.4.23.50     
Accepted name: human endogenous retrovirus K endopeptidase
Reaction: Processing at the authentic HIV-1 PR recognition site and release of the mature p17 matrix and the p24 capsid protein, as a result of the cleavage of the -SQNY┼PIVQ- cleavage site.
Other name(s): human endogenous retrovirus K10 endopeptidase; endogenous retrovirus HERV-K10 putative protease; human endogenous retrovirus K retropepsin; HERV K10 endopeptidase; HERV K10 retropepsin; HERV-K PR; HERV-K protease; HERV-K113 protease; human endogenous retrovirus K113 protease; human retrovirus K10 retropepsin
Comments: In peptidase family A2.
References:
1.  Towler, E.M., Gulnik, S.V., Bhat, T.N., Xie, D., Gustschina, E., Sumpter, T.R., Robertson, N., Jones, C., Sauter, M., Mueller-Lantzsch, N., Debouck, C. and Erickson, J.W. Functional characterization of the protease of human endogenous retrovirus, K10: can it complement HIV-1 protease. Biochemistry 37 (1998) 17137–17144. [PMID: 9860826]
[EC 3.4.23.50 created 2009]
 
 
EC 3.4.23.51     
Accepted name: HycI peptidase
Reaction: This enzyme specifically removes a 32-amino acid peptide from the C-terminus of the precursor of the large subunit of hydrogenase 3 in Escherichia coli by cleavage at the C-terminal side of Arg537.
Other name(s): HycI; HycE processing protein
Comments: The reaction requires nickel to be bound to the precursor of the large subunit of hydrogenase 3. The endopeptidase uses the metal in the large subunit of [NiFe]-hydrogenases as a recognition motif [1]. In peptidase family A31.
References:
1.  Theodoratou, E., Paschos, A., Magalon, A., Fritsche, E., Huber, R. and Bock, A. Nickel serves as a substrate recognition motif for the endopeptidase involved in hydrogenase maturation. Eur. J. Biochem. 267 (2000) 1995–1999. [PMID: 10727938]
2.  Yang, F., Hu, W., Xu, H., Li, C., Xia, B. and Jin, C. Solution structure and backbone dynamics of an endopeptidase HycI from Escherichia coli: implications for mechanism of the [NiFe] hydrogenase maturation. J. Biol. Chem. 282 (2007) 3856–3863. [PMID: 17150961]
[EC 3.4.23.51 created 2009]
 
 
EC 3.4.23.52     
Accepted name: preflagellin peptidase
Reaction: Cleaves the signal peptide of 3 to 12 amino acids from the N-terminal of preflagellin, usually at Arg-Gly┼ or Lys-Gly┼, to release flagellin.
Other name(s): FlaK
Comments: An aspartic peptidase from Archaea but not bacteria. In peptidase family A24 (type IV prepilin peptidase family).
References:
1.  Bardy, S.L. and Jarrell, K.F. FlaK of the archaeon Methanococcus maripaludis possesses preflagellin peptidase activity. FEMS Microbiol. Lett. 208 (2002) 53–59. [PMID: 11934494]
2.  Ng, S.Y., VanDyke, D.J., Chaban, B., Wu, J., Nosaka, Y., Aizawa, S. and Jarrell, K.F. Different minimal signal peptide lengths recognized by the archaeal prepilin-like peptidases FlaK and PibD. J. Bacteriol. 191 (2009) 6732–6740. [PMID: 19717585]
3.  Hu, J., Xue, Y., Lee, S. and Ha, Y. The crystal structure of GXGD membrane protease FlaK. Nature 475 (2011) 528–531. [PMID: 21765428]
[EC 3.4.23.52 created 2011]
 
 
EC 3.4.24.1     
Accepted name: atrolysin A
Reaction: Cleavage of Asn3┼Gln, His5┼Leu, His10┼Leu, Ala14┼Leu and Tyr16┼Leu in insulin B chain; removes C-terminal Leu from small peptides
Other name(s): Crotalus atrox metalloendopeptidase a; hemorrhagic toxin a; Crotalus atrox α-proteinase; Crotalus atrox proteinase; bothropasin
Comments: A hemorrhagic endopeptidase of 68 kDa, one of six hemorrhagic toxins in the venom of western diamondback rattlesnake. The 60 kDa hemorrhagic toxin 1 of Crotalus ruber ruber shows identical specificity [2]. In peptidase family M12 (astacin family). Related metalloendopeptidases from rattlesnake venoms are EC 3.4.24.41 (atrolysin B), EC 3.4.24.42 (atrolysin C), EC 3.4.24.43 (atroxase), EC 3.4.24.44 (atrolysin E), EC 3.4.24.45 (atrolysin F), EC 3.4.24.46 (adamalysin), EC 3.4.24.47 (horrilysin), and EC 3.4.24.48 (ruberlysin)
References:
1.  Bjarnason, J.B. and Tu, A.T. Hemorrhagic toxins from western diamondback rattlesnake (Crotalus atrox) venom: isolation and characterization of five toxins and the role of zinc in hemorrhagic toxin e. Biochemistry 17 (1978) 3395–3404. [PMID: 210790]
2.  Mori, N., Nikai, T., Sugihara, H. and Tu, A.T. Biochemical characterization of hemorrhagic toxins with fibrinogenase activity isolated from Crotalus ruber ruber venom. Arch. Biochem. Biophys. 253 (1987) 108–121. [PMID: 2949699]
3.  Bjarnason, J.B., Hamilton, D. and Fox, J.W. Studies on the mechanism of hemorrhage production by five proteolytic hemorrhagic toxins from Crotalus atrox venom. Biol. Chem. Hoppe-Seyler 369 (1988) 121–129. [PMID: 3060135]
4.  Bjarnason, J.B. and Fox, J.W. Hemorrhagic toxins from snake venoms. J. Toxicol. Toxin Rev. 7 (1989) 121–209.
[EC 3.4.24.1 created 1972, modified 1986]
 
 
EC 3.4.24.2      
Deleted entry: Sepia proteinase
[EC 3.4.24.2 created 1972, deleted 1992]
 
 
EC 3.4.24.3     
Accepted name: microbial collagenase
Reaction: Digestion of native collagen in the triple helical region at ┼Gly bonds. With synthetic peptides, a preference is shown for Gly at P3 and P1′, Pro and Ala at P2 and P2′, and hydroxyproline, Ala or Arg at P3′
Other name(s): Clostridium histolyticum collagenase; clostridiopeptidase A; collagenase A; collagenase I; Achromobacter iophagus collagenase; collagenase; aspergillopeptidase C; nucleolysin; azocollase; metallocollagenase; soycollagestin; Clostridium histolyticum proteinase A; clostridiopeptidase II; MMP-8; clostridiopeptidase I; collagen peptidase; collagen protease; collagenase MMP-1; metalloproteinase-1; kollaza; matrix metalloproteinase-1; MMP-1; matrix metalloproteinase-8; matirx metalloproteinase-18; interstitial collagenase
Comments: Six species of metalloendopeptidase acting on native collagen can be isolated from the medium of Clostridium histolyticum. Class I has forms α (68 kDa), β (115 kDa) and γ (79 kDa); class II has δ (100 kDa), ε (110 kDa) and ζ (125 kDa). The two classes are immunologically crossreactive, but have significantly different sequences, and different specificities such that their actions on collagen are complementary. The enzymes also act as peptidyl-tripeptidases. Variants of the enzyme have been purified from Bacillus cereus [10], Empedobacter collagenolyticum [4], Pseudomonas marinoglutinosa [1], and species of Vibrio, Vibrio B-30 (ATCC 21250) [2] and V. alginolyticus (previously Achromobacter iophagus) [3,8]. Also known from Streptomyces sp. [9]. The Vibrio enzyme is the type example of peptidase family M9.
References:
1.  Hanada, K., Mizutani, T., Yamagishi, M., Tsuji, H., Misaki, T. Sawada, J. The isolation of collagenase and its enzymological and physico-chemical properties. Agric. Biol. Chem. 37 (1973) 1771–1781.
2.  Merkel, J.R. and Dreisbach, J.H. Purification and characterization of a marine bacterial collagenase. Biochemistry 17 (1978) 2857–2863. [PMID: 210785]
3.  Heindl, M.-C., Fermandjian, S. and Keil, B. Circular dichroism comparative studies of two bacterial collagenases and thermolysin. Biochim. Biophys. Acta 624 (1980) 51–59. [PMID: 6250633]
4.  Labadie, J. and Montel, M..-C. Purification et étude de quelques propriétés d’une collagénase produite par Empedobacter collagenolyticum. Biochimie 64 (1982) 49–54. [PMID: 6530724]
5.  Bond, M.D and Van Wart, H.D. Characterization of the individual collagenases from Clostridium histolyticum. Biochemistry 23 (1984) 3085–3091. [PMID: 6087888]
6.  Bond, M.D. and Van Wart, H.D. Relationship between the individual collagenases of Clostridium histolyticum: evidience for evolution by gene duplication. Biochemistry 23 (1984) 3092–3099. [PMID: 6087889]
7.  Van Wart, H.D. and Steinbrink, D.R. Complementary substrate specificities of class I and class II collagenases from Clostridium histolyticum. Biochemistry 24 (1985) 6520–6526. [PMID: 3002445]
8.  Tong, N.T., Tsugita, A. and Keil-Dlouha, V. Purification and characterization of two high-molecular-mass forms of Achromobacter collagenase. Biochim. Biophys. Acta 874 (1986) 296–304.
9.  Endo, A., Murakawa, S., Shimizu, H. and Shiraishi, Y. Purification and properties of collagenase from a Streptomyces species. J. Biochem. (Tokyo) 102 (1987) 163–170. [PMID: 2822678]
10.  Makinen, K.K. and Makinen, P.-L. Purification and properties of an extracellular collagenolytic protease produced by the human oral bacterium Bacillus cereus (strain Soc 67). J. Biol. Chem. 262 (1987) 12488–12495. [PMID: 3040751]
[EC 3.4.24.3 created 1961 as EC 3.4.4.19, transferred 1972 to EC 3.4.24.3 (EC 3.4.24.8 created 1978, incorporated 1992, EC 3.4.99.5 created 1972, incorporated 1978)]
 
 
EC 3.4.24.4      
Transferred entry: now EC 3.4.24.40 serralysin
[EC 3.4.24.4 created 1972 [EC 3.4.99.13 and EC 3.4.99.22 both created 1972, incorporated 1978], deleted 1992]
 
 
EC 3.4.24.5      
Deleted entry:  lens neutral proteinase. Now included with EC 3.4.22.53 (calpain-2) and EC 3.4.25.1 (proteasome endopeptidase complex)
[EC 3.4.24.5 created 1978, deleted 1989]
 
 
EC 3.4.24.6     
Accepted name: leucolysin
Reaction: Cleavage of Phe1┼Val, His5┼Leu, Ala14┼Leu, Gly20┼Glu, Gly23┼Phe and Phe24┼Phe bonds in insulin B chain as well as N-blocked dipeptides
Other name(s): Leucostoma neutral proteinase; Leucostoma peptidase A
Comments: From the venom of the western cottonmouth moccasin snake (Agkistrodon piscivorus leucostoma).
References:
1.  Wagner, F.W., Spiekerman, A.M. and Prescott, J.M. Leucostoma peptidase A. Isolation and physical properties. J. Biol. Chem. 243 (1968) 4486–4493. [PMID: 5684005]
2.  Spiekerman, A.M., Fredericks, K.K., Wagner, F.W. and Prescott, J.M. Leucostoma peptidase A: a metalloprotease from snake venom. Biochim. Biophys. Acta 293 (1973) 464–475. [PMID: 4711816]
[EC 3.4.24.6 created 1978]
 
 
EC 3.4.24.7     
Accepted name: interstitial collagenase
Reaction: Cleavage of the triple helix of collagen at about three-quarters of the length of the molecule from the N-terminus, at Gly775┼Ile in the α1(I) chain. Cleaves synthetic substrates and α-macroglobulins at bonds where P1′ is a hydrophobic residue
Other name(s): vertebrate collagenase; matrix metalloproteinase 1
Comments: The enzyme takes its name from substrates of the interstitial collagen group - types I, II and III, all of which are cleaved in the helical domain. However, α-macroglobulins are cleaved much more rapidly. The enzyme is widely distributed in vertebrate animals. Type example of peptidase family M10
References:
1.  Goldberg, G.I., Wilhelm, S.M., Kronberger, A., Bauer, E.A., Grant, G.A. and Eisen, A.Z. Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. J. Biol. Chem. 261 (1986) 6600–6605. [PMID: 3009463]
2.  Birkedal-Hansen, H. Catabolism and turnover of collagens: collagenases. Methods Enzymol. 144 (1987) 140–171. [PMID: 3041177]
3.  Fields, G.B., Van Wart, H.E. and Birkedal-Hansen, H. Sequence specificity of human skin fibroblast collagenase. Evidence for the role of collagen structure in determining the collagenase cleavage site. J. Biol. Chem. 262 (1987) 6221–6226. [PMID: 3032960]
4.  Sottrup-Jensen, L. and Birkedal-Hansen, H. Human fibroblast collagenase-α-macroglobulin interactions. Localization of cleavage sites in the bait regions of five mammalian α-macroglobulins. J. Biol. Chem. 264 (1989) 393–401. [PMID: 2462561]
[EC 3.4.24.7 created 1978]
 
 
EC 3.4.24.8      
Transferred entry: Achromobacter iophagus collagenase. Now EC 3.4.24.3, microbial collagenase
[EC 3.4.24.8 created 1978, deleted 1992]
 
 
EC 3.4.24.9      
Deleted entry:  Trichophyton schoenleinii collagenase
[EC 3.4.24.9 created 1978, deleted 1992]
 
 
EC 3.4.24.10      
Deleted entry: Trichophyton mentagrophytes keratinase
[EC 3.4.24.10 created 1972 as EC 3.4.99.12, transferred 1978 to EC 3.4.24.10, deleted 1992]
 
 
EC 3.4.24.11     
Accepted name: neprilysin
Reaction: Preferential cleavage of polypeptides between hydrophobic residues, particularly with Phe or Tyr at P1′
Other name(s): neutral endopeptidase; endopeptidase 24.11; kidney-brush-border neutral peptidase; enkephalinase (misleading); endopeptidase-2; CALLA (common acute lymphoblastic leukemia-associated) antigens; CALLA antigen; endopeptidase; membrane metalloendopeptidase; kidney-brush-border neutral endopeptidase; kidney-brush-border neutral proteinase; endopeptidase-2; CALLA glycoprotein; CALLA; common acute lymphoblastic leukemia antigen; CALLA glycoproteins; common acute lymphoblastic leukemia-associated antigens; neutral metallendopeptidase; membrane metalloendopeptidase; NEP; neutral endopeptidase 24.11; CD10; neutral endopeptidase; acute lymphoblastic leukemia antigen
Comments: A membrane-bound glycoprotein widely distributed in animal tissues. Inhibited by phosphoramidon and thiorphan. Common acute lymphoblastic leukemia antigen (CALLA). Type example of peptidase family M13
References:
1.  Matsas, R., Fulcher, I.S., Kenny, A.J. and Turner, A.J. Substance P and [Leu]enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli. Proc. Natl Acad. Sci. USA 80 (1983) 3111–3115. [PMID: 6190172]
2.  Malfroy, B., Schofield, P.R., Kuang, W.-J., Seeburg, P.H., Mason, A.J. Henzel, W.J. Molecular cloning and amino acid sequence of rat enkephalinase. Biochem. Biophys. Res. Commun. 144 (1987) 59–66. [PMID: 3555489]
3.  Letarte, M., Vera, S., Tran, R., Addis, J.B.L., Onizuka, R.J., Quackenbush, E J., Jongneel, C.V. and McInnes, R.R. Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. J. Exp. Med. 168 (1988) 1247–1253. [PMID: 2971756]
4.  Erdös, E.G. and Skidgel, R.A. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J. 3 (1989) 145–151. [PMID: 2521610]
[EC 3.4.24.11 created 1978, modified 1989]
 
 
EC 3.4.24.12     
Accepted name: envelysin
Reaction: Hydrolysis of proteins of the fertilization envelope and dimethylcasein
Other name(s): sea-urchin-hatching proteinase; hatching enzyme; chorionase; chorion-digesting proteinase; chymostrypsin; sea urchin embryo hatching enzyme
Comments: A glycoprotein from various members of the class Echinoidea. Extracellular enzyme requiring Ca2+. In peptidase family M10 (interstitial collagenase family)
References:
1.  Barrett, D. and Edwards, B.F. Hatching enzyme of the sea urchin Strongylocentrotus purpuratus. Methods Enzymol. 45 (1976) 354–373. [PMID: 1012003]
2.  Lepage, T. and Gache, C. Purification and characterization of the sea urchin embryo hatching enzyme. J. Biol. Chem. 264 (1989) 4787–4793. [PMID: 2925668]
3.  Lepage, T. and Gache, C. Early expression of a collagenase-like hatching enzyme gene in the sea urchin embryo. EMBO J. 9 (1990) 3003–3012. [PMID: 2167841]
4.  Nomura, K., Tanaka, H., Kikkawa, Y., Yamaguchi, M. and Suzuki, N. The specificity of sea urchin hatching enzyme (envelysin) places it in the mammalian matrix metalloproteinase family. Biochemistry 30 (1991) 6115–6123. [PMID: 1711895]
[EC 3.4.24.12 created 1978]
 
 
EC 3.4.24.13     
Accepted name: IgA-specific metalloendopeptidase
Reaction: Cleavage of Pro┼Thr bond in the hinge region of the heavy chain of human IgA
Other name(s): immunoglobulin A1 proteinase; IgA protease; IgA1-specific proteinase; IgA1 protease; IgA1 proteinase
Comments: A 190 kDa enzyme found in several pathogenic species of Streptococcus such as sanguis and pneumoniae. Type example of peptidase family M26. There is also an IgA-specific prolyl endopeptidase of the serine-type (see EC 3.4.21.72, IgA-specific serine endopeptidase)
References:
1.  Kornfeld, S.J. and Plaut, A.G. Secretory immunity and the bacterial IgA proteases. Rev. Infect. Dis. 3 (1981) 521–534. [PMID: 6792682]
2.  Gilbert, J.V., Plaut, A.G. and Wright, A. Analysis of the immunoglobulin A protease gene of Streptococcus sanguis. Infect. Immun. 59 (1991) 7–17. [PMID: 1987065]
3.  Gilbert, J.V., Plaut, A.G., Fishman, Y. and Wright, A. Cloning of the gene encoding streptococcal immunoglobulin A protease and its expression in Escherichia coli. Infect. Immun. 56 (1988) 1961–1966. [PMID: 3294181]
[EC 3.4.24.13 created 1984]
 
 
EC 3.4.24.14     
Accepted name: procollagen N-endopeptidase
Reaction: Cleaves the N-propeptide of collagen chain α1(I) at Pro┼Gln and of α1(II) and α2(I) at Ala┼Gln
Other name(s): procollagen N-terminal peptidase; procollagen aminopeptidase; aminoprocollagen peptidase; aminoterminal procollagen peptidase; procollagen aminoterminal protease; procollagen N-terminal proteinase; type I/II procollagen N-proteinase; type III procollagen
Comments: Removes the propeptides of type I and II collagens prior to fibril assembly. Does not act on type III collagen. In peptidase family M12 (astacin family)
References:
1.  Kohn, L.D., Iserky, C., Zupnik, J., Lenaers, A., Lee, G. and Lapiére, C.M. Calf tendon procollagen peptidase: its purification and endopeptidase mode of action. Proc. Natl. Acad. Sci. USA 71 (1974) 40–44. [PMID: 4204204]
2.  Hojima, Y., McKenzie, J., van der Rest, M. and Prockop, D.J. Type I procollagen N-proteinase from chick embryo tendons. Purification of a new 500-kDa form of the enzyme and identification of the catalytically active polypeptides. J. Biol. Chem. 264 (1989) 11336–11345. [PMID: 2500439]
[EC 3.4.24.14 created 1984]
 
 
EC 3.4.24.15     
Accepted name: thimet oligopeptidase
Reaction: Preferential cleavage of bonds with hydrophobic residues at P1, P2 and P3′ and a small residue at P1′ in substrates of 5-15 residues
Other name(s): Pz-peptidase; soluble metalloendopeptidase; endo-oligopeptidase A; tissue-endopeptidase degrading collagenase-synthetic-substrate
Comments: Thiol compounds activate at low concentrations. Type example of peptidase family M3.
References:
1.  Cicilini, M.A., Ribeiro, M.J.F., de Oliveira, E.B., Mortara, R.A. and de Camargo, A.C.M. Endooligopeptidase A activity in rabbit heart: generation of enkephalin from enkephalin containing peptides. Peptides (Fayetteville) 9 (1988) 945–955. [PMID: 3244563]
2.  Orlowski, M., Reznik, S., Ayala, J. and Pierotti, A.R. Endopeptidase 24.15 from rat testes. Isolation of the enzyme and its specificity toward synthetic and natural peptides, including enkephalin-containing peptides. Biochem. J. 261 (1989) 951–958. [PMID: 2803255]
3.  Barrett, A.J. and Brown, M.A. Chicken liver Pz-peptidase, a thiol-dependent metallo-endopeptidase. Biochem. J. 271 (1990) 701–706. [PMID: 2123097]
4.  Pierotti, A., Dong, K.W., Glucksman, M.J., Orlowski, M. and Roberts, J.L. Molecular cloning and primary structure of rat testes metalloendopeptidase EC 3.4.24.15. Biochemistry 29 (1990) 10323–10329. [PMID: 2261476]
5.  Tisljar, U. and Barrett, A.J. Thiol-dependent metallo-endopeptidase characteristics of Pz-peptidase in rat and rabbit. Biochem. J. 267 (1990) 531–533. [PMID: 2185743]
[EC 3.4.24.15 created 1984 (EC 3.4.22.19 created 1989 and EC 3.4.99.31 created 1978 both incorporated 1992)]
 
 
EC 3.4.24.16     
Accepted name: neurolysin
Reaction: Preferential cleavage in neurotensin: Pro10┼Tyr
Other name(s): neurotensin endopeptidase; endopeptidase 24.16; endo-oligopeptidase B (proline-endopeptidase)
Comments: No absolute requirement for a prolyl bond: the enzyme acts on some peptides, such as dynorphin 1-8, that do not contain proline, and does not act on some others that do. In peptidase family M3 (thimet oligopeptidase family)
References:
1.  Checler, F., Vincent, J.P. and Kitabgi, P. Purification and characterization of a novel neurotensin-degrading peptidase from rat brain synaptic membranes. J. Biol. Chem. 261 (1986) 11274–11281. [PMID: 3525564]
2.  Barelli, H., Vincent, J.-P. and Checler, F. Peripheral inactivation of neurotensin. Isolation and characterization of a metallopeptidase from rat ileum. Eur. J. Biochem. 175 (1988) 481–489. [PMID: 3409880]
3.  Checler, F., Barelli, H. and Vincent, J.-P. Tissue distribution of a novel neurotensin-degrading metallopeptidase. An immunological approach using monospecific polyclonal antibodies. Biochem. J. 257 (1989) 549–554. [PMID: 2649078]
[EC 3.4.24.16 created 1989]
 
 
EC 3.4.24.17     
Accepted name: stromelysin 1
Reaction: Preferential cleavage where P1′, P2′ and P3′ are hydrophobic residues
Other name(s): matrix metalloproteinase 3; proteoglycanase; collagenase activating protein; procollagenase activator; transin; MMP-3; neutral proteoglycanase; stromelysin; collagen-activating protein
Comments: An extracellular endopeptidase of vertebrate tissues homologous with interstitial collagenase. Digests proteoglycan, fibronectin, collagen types III, IV, V, IX, and activates procollagenase. In peptidase family M10 (interstitial collagenase family)
References:
1.  Chin, J.R., Murphy, G. and Werb, Z. Stromelysin, a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization, and substrates. J. Biol. Chem. 260 (1985) 12367–12376. [PMID: 2995374]
2.  Okada, Y., Nagase, H. and Harris, E.D., Jr. A metalloproteinase from human rheumatoid synovial fibroblasts that digests connective tissue matrix components. Purification and characterization. J. Biol. Chem. 261 (1986) 14245–14255. [PMID: 3095317]
3.  Docherty, A.J.P. and Murphy, G. The tissue metalloproteinase family and the inhibitor TIMP: a study using cDNAs and recombinant proteins. Ann. Rheum. Dis. 49 (1990) 469–479. [PMID: 2197998]
4.  Emonard, H. and Grimaud, J.-A. Matrix metalloproteinase. A review. Cell. Mol. Biol. 36 (1990) 131–153. [PMID: 2165861]
[EC 3.4.24.17 created 1990]
 
 
EC 3.4.24.18     
Accepted name: meprin A
Reaction: Hydrolysis of protein and peptide substrates preferentially on carboxyl side of hydrophobic residues
Other name(s): endopeptidase-2; meprin-a; meprin; N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase; PABA-peptide hydrolase; PPH
Comments: A membrane-bound metalloendopeptidase of rat and mouse kidney and intestinal brush borders, and salivary ducts. Differences from neprilysin (EC 3.4.24.11 (astacin family). Formerly included in EC 3.4.24.11
References:
1.  Beynon, R.J., Shannon, J.D. and Bond, J.S. Purification and characterization of a metallo-endoproteinase from mouse kidney. Biochem. J. 199 (1981) 591–598. [PMID: 7041888]
2.  Butler, P.E., McKay, M.J. and Bond, J.S. Characterization of meprin, a membrane-bound metalloendopeptidase from mouse kidney. Biochem. J. 241 (1987) 229–235. [PMID: 3105525]
3.  Stephenson, S.L. and Kenny, A.J. The metabolism of neuropeptides. Hydrolysis of peptides by the phosphoramidon-insensitive rat kidney enzyme 'endopeptidase-2′ and by rat microvillar membranes. Biochem. J. 255 (1988) 45–51. [PMID: 2461706]
4.  Sterchi, E.E., Naim, H.Y., Lentze, M.J., Hauri, H.-P. Fransen, J.A.M. N-Benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase: a metalloendopeptidase of the human intestinal microvillus membrane which degrades biologically active peptides. Arch. Biochem. Biophys. 265 (1988) 105–118. [PMID: 3261961]
5.  Barnes, K., Ingram, J. and Kenny, A.J. Proteins of the kidney microvillar membrane. Structural and immunochemical properties of rat endopeptidase-2 and its immunohistochemical localization in tissues of rat and mouse. Biochem. J. 264 (1989) 335–346. [PMID: 2690825]
[EC 3.4.24.18 created 1992]
 
 
EC 3.4.24.19     
Accepted name: procollagen C-endopeptidase
Reaction: Cleavage of the C-terminal propeptide at Ala┼Asp in type I and II procollagens and at Arg┼Asp in type III
Other name(s): procollagen C-terminal proteinase; carboxyprocollagen peptidase; procollagen C-terminal peptidase; procollagen C-proteinase; procollagen C-terminal proteinase; procollagen carboxypeptidase; procollagen carboxy-terminal proteinase; procollagen peptidase
Comments: A 100 kDa endopeptidase the activity of which is increased by Ca2+ and by an enhancer glycoprotein. In peptidase family M12 (astacin family)
References:
1.  Hojima, Y., van der Rest, M. and Prockop, D.J. Type I procollagen carboxyl-terminal proteinase from chick embryo tendons. Purification and characterization. J. Biol. Chem. 260 (1985) 15996–16003. [PMID: 3905801]
2.  Kessler, E. and Adar, R. Type I procollagen C-proteinase from mouse fibroblasts. Purification and demonstration of a 55-kDa enhancer glycoprotein. Eur. J. Biochem. 186 (1989) 115–121. [PMID: 2689170]
[EC 3.4.24.19 created 1992]
 
 
EC 3.4.24.20     
Accepted name: peptidyl-Lys metalloendopeptidase
Reaction: Preferential cleavage in proteins: -Xaa┼Lys- (in which Xaa may be Pro)
Other name(s): Armillaria mellea neutral proteinase; peptidyllysine metalloproteinase
Comments: From the honey fungus Armillaria mellea. In peptidase family M35 (deuterolysin family).
References:
1.  Doonan S, Doonan HJ, Hanford R, Vernon CA, Walker JM, da Airold LP, Bossa F, Barra D, Carloni M, Fasella P, Riva F. The primary structure of aspartate aminotransferase from pig heart muscle. Digestion with a proteinase having specificity for lysine residues. Biochem. J. 149 (1975) 497–506. [PMID: 1239277]
2.  Lewis, W.G., Basford, J.M. and Walton, P.L. Specificity and inhibition studies of Armillaria mellea protease. Biochim. Biophys. Acta 522 (1978) 551–560. [PMID: 23849]
[EC 3.4.24.20 created 1978 as EC 3.4.99.32, transferred 1992 to EC 3.4.24.20 (EC 3.4.99.30 created 1978, incorporated 1992)]
 
 
EC 3.4.24.21     
Accepted name: astacin
Reaction: Hydrolysis of peptide bonds in substrates containing five or more amino acids, preferentially with Ala in P1′, and Pro in P2′
Other name(s): Astacus proteinase; crayfish small-molecule proteinase
Comments: A 22.6 kDa digestive endopeptidase from the cardia of the crayfish Astacus fluviatilis. Type example of peptidase family M12.
References:
1.  Krauhs, E., Dörsam, H., Little, M., Zwilling, R. and Ponstingl, H. A protease from Astacus fluviatilis as an aid in protein sequencing. Anal. Biochem. 119 (1982) 153–157. [PMID: 7041692]
2.  Titani, K., Torff, H.-J., Hormel, S., Kumar, S., Walsh, K.A., Rödl, J., Neurath, H. and Zwilling, R. Amino acid sequence of a unique protease from the crayfish Astacus fluviatilis. Biochemistry 26 (1987) 222–226. [PMID: 3548817]
3.  Stöcker, W., Wolz, R.L., Zwilling, R., Strydom, D.J. and Auld, D.S. Astacus protease, a zinc metalloenzyme. Biochemistry 27 (1988) 5026–5032.
4.  Stöcker, W., Ng, M. and Auld, D.S. Fluorescent oligopeptide substrates for kinetic characterization of the specificity of Astacus protease. Biochemistry 29 (1990) 10418–10425. [PMID: 2261483]
[EC 3.4.24.21 created 1972 as EC 3.4.99.6, transferred 1992 to EC 3.4.24.21]
 
 
EC 3.4.24.22     
Accepted name: stromelysin 2
Reaction: Similar to stromelysin 1, but action on collagen types III, IV and V is weak
Other name(s): matrix metalloproteinase 10; transin 2; proteoglycanase 2
Comments: In peptidase family M10 (interstitial collagenase family). Digests gelatin types I, III, IV, V, fibronectin and proteoglycan
References:
1.  Breathnach, R., Matrisian, L.M., Gesnel, M.-C. and Leroy, P. Sequences coding for part of oncogene-induced transin are highly conserved in a related rat gene. Nucleic Acids Res. 15 (1987) 1139–1151. [PMID: 3547333]
2.  Muller, D., Quantin, B., Gesnel, M.-C., Millon-Collard, R., Abecassis, J. and Breathnach, R. The collagenase gene family in humans consists of at least four members. Biochem. J. 253 (1988) 187–192. [PMID: 2844164]
3.  Nicholson, R., Murphy, G. and Breathnach, R. Human and rat malignant-tumor-associated mRNAs encode stromelysin-like metalloproteinases. Biochemistry 28 (1989) 5195–5203. [PMID: 2548603]
[EC 3.4.24.22 created 1992]
 
 
EC 3.4.24.23     
Accepted name: matrilysin
Reaction: Cleavage of Ala14┼Leu and Tyr16┼Leu in B chain of insulin. No action on collagen types I, II, IV, V. Cleaves gelatin chain α2(I) > α1(I)
Other name(s): matrin; uterine metalloendopeptidase; matrix metalloproteinase 7; putative (or punctuated) metalloproteinase-1; matrix metalloproteinase pump 1; MMP 7; PUMP-1 proteinase; PUMP; metalloproteinase pump-1; putative metalloproteinase; MMP
Comments: Found in rat uterus; at 19 kDa, the smallest member of peptidase family M10 (interstitial collagenase family). Similar in specificity to stromelysin, but more active on azocoll
References:
1.  Muller, D., Quantin, B., Gesnel, M.-C., Millon-Collard, R., Abecassis, J. and Breathnach, R. The collagenase gene family in humans consists of at least four members. Biochem. J. 253 (1988) 187–192. [PMID: 2844164]
2.  Woessner, J.F., Jr. and Taplin, C.J. Purification and properties of a small latent matrix metalloproteinase of the rat uterus. J. Biol. Chem. 263 (1988) 16918–16925. [PMID: 3182822]
3.  Quantin, B., Murphy, G. and Breathnach, R. Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. Biochemistry 28 (1989) 5327–5334. [PMID: 2550050]
4.  Miyazaki, K., Hattori, Y., Umenishi, F., Yasumitsu, H. and Umeda, M. Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line. Cancer Res. 50 (1990) 7758–7764. [PMID: 2253219]
[EC 3.4.24.23 created 1992]
 
 
EC 3.4.24.24     
Accepted name: gelatinase A
Reaction: Cleavage of gelatin type I and collagen types IV, V, VII, X. Cleaves the collagen-like sequence Pro-Gln-Gly┼Ile-Ala-Gly-Gln
Other name(s): 72-kDa gelatinase; matrix metalloproteinase 2; type IV collagenase (ambiguous); 3/4 collagenase (obsolete); matrix metalloproteinase 5 (obsolete); 72 kDa gelatinase type A; collagenase IV (ambiguous); collagenase type IV (ambiguous); MMP 2; type IV collagen metalloproteinase (ambiguous); type IV collagenase/gelatinase (ambiguous)
Comments: A secreted endopeptidase in peptidase family M10 (interstitial collagenase family), but possessing an additional fibronectin-like domain
References:
1.  Murphy, G., McAlpine, C.G., Poll, C.T. and Reynolds, J.J. Purification and characterization of a bone metalloproteinase that degrades gelatin and types IV and V collagen. Biochim. Biophys. Acta 831 (1985) 49–58. [PMID: 2994741]
2.  Collier, I.E., Wilhelm, S.M., Eisen, A.Z., Marmer, B.L., Grant, G.A., Seltzer, J.L., Kronberger, A., He, C., Bauer, E.A. and Goldberg, G.I. H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J. Biol. Chem. 263 (1988) 6579–6587. [PMID: 2834383]
3.  Okada, Y., Morodomi, T., Enghild, J.J., Suzuki, K., Yasui, A., Nakanishi, I., Salvesen, G. and Nagase, H. Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts-purification and activation of the precursor and enzymic properties. Eur. J. Biochem. 194 (1990) 721–730. [PMID: 2269296]
[EC 3.4.24.24 created 1992]
 
 
EC 3.4.24.25     
Accepted name: vibriolysin
Reaction: Preferential cleavage of bonds with bulky hydrophobic groups in P2 and P1′. Phe at P1′ is the most favoured residue, which distinguished this enzyme from thermolysin
Other name(s): Aeromonas proteolytica neutral proteinase; aeromonolysin
Comments: Thermostable enzyme from Vibrio proteolyticus (formerly Aeromonas proteolytica). Specificity related to, but distinct from, those of thermolysin and bacillolysin [1]. A zinc metallopeptidase in family M4 (thermolysin family). Formerly included in EC 3.4.24.4
References:
1.  Holmquist, B. and Vallee, B.L. Esterase activity of zinc neutral proteases. Biochemistry 15 (1976) 101–107. [PMID: 2276]
2.  Wilkes, S.H. and Prescott, J.M. Aeromonas neutral protease. Methods Enzymol. 45 (1976) 404–415. [PMID: 1012006]
3.  Bayliss, M.E., Wilkes, S.H. and Prescott, J.M. Aeromonas neutral protease: specificity toward extended substrates. Arch. Biochem. Biophys. 204 (1980) 214–219. [PMID: 7000005]
4.  Wilkes, S.H., Bayliss, M.E. and Prescott, J.M. Critical ionizing groups in Aeromonas neutral protease. J. Biol. Chem. 263 (1988) 1821–1825. [PMID: 3123480]
5.  David, V.A., Deutch, A.H., Sloma, A., Pawlyk, D., Ally, A. and Durham, D.R. Cloning, sequencing and expression of the gene encoding the extracellular neutral protease, vibriolysin, of Vibrio proteolyticus. Gene 112 (1992) 107–112. [PMID: 1551587]
[EC 3.4.24.25 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.25, modified 1997]
 
 
EC 3.4.24.26     
Accepted name: pseudolysin
Reaction: Hydrolysis of proteins including elastin, collagen types III and IV, fibronectin and immunoglobulin A, generally with bulky hydrophobic group at P1′. Insulin B chain cleavage pattern identical to that of thermolysin, but specificity differs in other respects
Other name(s): Pseudomonas elastase; Pseudomonas aeruginosa neutral metalloproteinase
Comments: In peptidase family M4 (thermolysin family). From the pathogenic bacteria Pseudomonas aeruginosa and Legionella pneumophila, and causes tissue damage.
References:
1.  Morihara, K. and Tsuzuki, H. Pseudomonas aeruginosa elastase: affinity chromatography and some properties as a metallo-neutral proteinase. Agric. Biol. Chem. 39 (1975) 1123–1128.
2.  Nishino, N. and Powers, J.C. Pseudomonas aeruginosa elastase. Development of a new substrate, inhibitors, and an affinity ligand. J. Biol. Chem. 255 (1980) 3482–3486. [PMID: 6767718]
3.  Dreyfus, L.A. and Iglewski, B.H. Purification and characterization of an extracellular protease of Legionella pneumophila. Infect. Immun. 70 (1986) 736–743. [PMID: 3512431]
4.  Bever, R.A. and Iglewski, B.H. Molecular characterization and nucleotide sequence of the Pseudomonas aeruginosa elastase structural gene. J. Bacteriol. 170 (1988) 4309–4314. [PMID: 2842313]
5.  Black, W.J., Quinn, F.D. and Tompkins, L.S. Legionella pneumophila zinc metalloprotease is structurally and functionally homologous to Pseudomonas aeruginosa elastase. J. Bacteriol. 172 (1990) 2608–2613. [PMID: 2110146]
[EC 3.4.24.26 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.26]
 
 
EC 3.4.24.27     
Accepted name: thermolysin
Reaction: Preferential cleavage: ┼Leu > ┼Phe
Other name(s): Bacillus thermoproteolyticus neutral proteinase; thermoase; thermoase Y10; TLN
Comments: A thermostable extracellular metalloendopeptidase containing four calcium ions. Enzymes that may be species variants of thermolysin are reported from Micrococcus caseolyticus [4] and Aspergillus oryzae [5]. Type example of peptidase family M4. Closely related but distinct enzymes are aeromonolysin, pseudolysin, bacillolysin, aureolysin and mycolysin
References:
1.  Ohta, Y. Ogura, Y. and Wada, A. Thermostable protease from thermophilic bacteria. I. Thermostability, physicochemical properties, and amino acid composition. J. Biol. Chem. 241 (1966) 5919–5925. [PMID: 5954368]
2.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [PMID: 4967801]
3.  Latt, S. A., Holmquist, B. and Vallee, B. L. Thermolysin: a zinc metalloenzyme. Biochem. Biophys. Res. Commun. 37 (1969) 333–339. [PMID: 5823940]
4.  Desmazeaud, M. J. and Hermier, J. H. Spécificité de la protéase neutre de Micrococcus caseolyticus. Eur. J. Biochem. 19 (1971) 51–55. [PMID: 5551628]
5.  Morihara, K. and Tsuzuki, H. Comparative study of various neutral proteinases from microorganisms: specificity with oligopeptides. Arch. Biochem. Biophys. 146 (1971) 291–296. [PMID: 5004124]
6.  Titani, K., Hermodson, M. A., Ericson, L. H., Walsh, K. A. and Neurath, H. Amino-acid sequence of thermolysin. Nature New Biol. 238 (1972) 35–37. [PMID: 18663848]
7.  Matthews, B. W. Structural basis of the action of thermolysin and related zinc peptidases. Acc. Chem. Res. 21 (1988) 333–340.
[EC 3.4.24.27 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.27]
 
 
EC 3.4.24.28     
Accepted name: bacillolysin
Reaction: Similar, but not identical, to that of thermolysin
Other name(s): Bacillus metalloendopeptidase; Bacillus subtilis neutral proteinase; anilozyme P 10; Bacillus metalloproteinase; Bacillus neutral proteinase; megateriopeptidase
Comments: Variants of this enzyme have been found in species of Bacillus including B. subtilis [1,6], B. amyloliquefaciens [5], B. megaterium (megateriopeptidase, [2]), B. mesentericus [10], B. cereus [3,8,9] and B. stearothermophilus [7]. In peptidase family M4 (thermolysin family). Formerly included in EC 3.4.24.4
References:
1.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [PMID: 4967801]
2.  Millet, J. and Acher, R. Spécificité de la mégatériopeptidase: une amino-endopeptidase à caractère hydrophobe. Eur. J. Biochem. 9 (1969) 456–462. [PMID: 4980359]
3.  Feder, J., Keay, L., Garrett, L.R., Cirulis, N., Moseley, M.H. and Wildi, B.S. Bacillus cereus neutral protease. Biochim. Biophys. Acta 251 (1971) 74–78. [PMID: 5002444]
4.  Holmquist, B. and Vallee, B.L. Esterase activity of zinc neutral proteases. Biochemistry 15 (1976) 101–107. [PMID: 2276]
5.  Vasantha, N., Thompson, L.D., Rhodes, C., Banner, C., Nagle, J. and Filpula, D. Genes for alkaline protease and neutral protease from Bacillus amyloliquefaciens contain a large open reading frame between the regions coding for signal sequence and mature protein. J. Bacteriol. 159 (1984) 811–819. [PMID: 6090391]
6.  Yang, M.Y., Ferrari, E. and Henner, D.J. Cloning of the neutral protease gene of Bacillus subtilis and the use of the cloned gene to create an in vitro-derived deletion mutation. J. Bacteriol. 160 (1984) 15–21. [PMID: 6090407]
7.  Takagi, M., Imanaka, T. and Aiba, S. Nucleotide sequence and promoter region for the neutral protease gene from Bacillus stearothermophilus. J. Bacteriol. 163 (1985) 824–831. [PMID: 2993245]
8.  Sidler, W., Niederer, E., Suter, F. and Zuber, H. The primary structure of Bacillus cereus neutral proteinase and comparison with thermolysin and Bacillus subtilis neutral proteinase. Biol. Chem. Hoppe-Seyler 367 (1986) 643–657. [PMID: 3092843]
9.  Pauptit, R.A., Karlson, R., Picot, D., Jenkins, J.A., Niklaus-Reimer, A.-S. and Jansonius, J.N. Crystal structure of neutral protease from Bacillus cereus refined at 3.0 Å resolution and comparison with the homologous but more thermostable enzyme thermolysin. J. Mol. Biol. 199 (1988) 525–537. [PMID: 3127592]
10.  Stoeva, S., Kleinschmidt, T., Mesrob, B. and Braunitzer, G. Primary structure of a zinc protease from Bacillus mesentericus strain 76. Biochemistry 29 (1990) 527–534. [PMID: 2302386]
[EC 3.4.24.28 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.28]
 
 
EC 3.4.24.29     
Accepted name: aureolysin
Reaction: Cleavage of insulin B chain with specificity similar to that of thermolysin, preferring hydrophobic P1′ residue. Activates the glutamyl endopeptidase (EC 3.4.21.19) of Staphylococcus aureus
Other name(s): Staphylococcus aureus neutral proteinase; Staphylococcus aureus neutral protease
Comments: A metalloenzyme from S. aureus earlier confused with staphylokinase (a non-enzymic activator of plasminogen).
References:
1.  Arvidson, S. Studies on extracellular proteolytic enzymes from Staphylococcus aureus. II. Isolation and characterization of an EDTA-sensitive protease. Biochim. Biophys. Acta 302 (1973) 149–157. [PMID: 4632563]
2.  Saheb, S.A. Purification et caractérisation d’une protéase extracellulaire de Staphylococcus aureus inhibée par l’E.D.T.A. Biochimie 58 (1976) 793–804. [PMID: 823980]
3.  Drapeau, G.R. Role of a metalloprotease in activation of the precursor of staphylococcal protease. J. Bacteriol. 136 (1978) 607–613. [PMID: 711676]
4.  Potempa, J., Porwit-Bohr, Z. and Travis, J. Stabilization vs. degradation of Staphylococcus aureus metalloproteinase. Biochim. Biophys. Acta 993 (1989) 301–304. [PMID: 2512988]
[EC 3.4.24.29 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.29]
 
 
EC 3.4.24.30     
Accepted name: coccolysin
Reaction: Preferential cleavage: ┼Leu, ┼Phe, ┼Tyr, ┼Ala
Other name(s): Streptococcus thermophilus intracellular proteinase; EM 19000
Comments: A 30 kDa endopeptidase found intracellularly in S. thermophilus [1] and S. diacetilactis [2] and in the medium of S. faecalis [3,4]. In peptidase family M4 (thermolysin family). Formerly included in EC 3.4.24.4
References:
1.  Desmazeaud, M.J. Propriétés générales et spécificité d’action d’une endopeptidase neutre intracellulaire de Streptococcus thermophilus. Biochimie 56 (1974) 1173–1181. [PMID: 4451671]
2.  Desmazeaud, M.J. and Zevaco, C. General properties and substrate specificity of an intracellular neutral protease from Streptococcus diacetilactis. Ann. Biol. Anim. Biochem. Biophys. 16 (1976) 851–868.
3.  Smith, R.A.G., Green, J. and Kopper, P.H. The purification and properties of a fibrinolytic neutral metalloendopeptidase from Streptococcus faecalis. Arch. Biochem. Biophys. 202 (1980) 629–638. [PMID: 6779709]
4.  Mäkinen, P.-L., Clewell, D.B., An, F., Mäkinen, K.K. Purification and substrate specificity of a strongly hydrophobic extracellular metalloendopeptidase ("gelatinase") from Streptococcus faecalis (strain 0G1-10). J. Biol. Chem. 264 (1989) 3325–3334. [PMID: 2536744]
[EC 3.4.24.30 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.30]
 
 
EC 3.4.24.31     
Accepted name: mycolysin
Reaction: Preferential cleavage of bonds with hydrophobic residues in P1′
Other name(s): pronase component; Streptomyces griseus neutral proteinase; actinase E; SGNPI
Comments: From Streptomyces griseus, S. naraensis, and S. cacaoi. Specificity similar to that of thermolysin, but much more sensitive to inhibition by mercaptoacetyl-Phe-Leu. Little structural similarity to other bacterial metalloendopeptidases. Type example of peptidase family M5. Formerly included in EC 3.4.24.4
References:
1.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [PMID: 4967801]
2.  Hiramatsu, A. and Ouchi, T. A neutral proteinase from Streptomyces naraensis. J. Biochem. (Tokyo) 71 (1972) 767–781. [PMID: 5073323]
3.  Blumberg, S. and Tauber, Z. Inhibition of metalloendopeptidases by 2-mercaptoacetyl-dipeptides. Eur. J. Biochem. 136 (1983) 151–154. [PMID: 6413206]
4.  Chang, P.C., Kue, T-C., Tsugita, A. and Lee, Y.H.W. Extracellular metalloprotease gene of Streptomyces cacaoi: structure, nucleotide sequence and characterization of the cloned gene product. Gene 88 (1990) 87–95. [PMID: 2341042]
[EC 3.4.24.31 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.31]
 
 
EC 3.4.24.32     
Accepted name: β-lytic metalloendopeptidase
Reaction: Cleavage of N-acetylmuramoyl┼Ala, and of the insulin B chain at Gly23┼Phe > Val18┼Cya
Other name(s): Myxobacter β-lytic proteinase; achromopeptidase component; β-lytic metalloproteinase; β-lytic protease; Myxobacterium sorangium β-lytic proteinase; Myxobacter495 β-lytic proteinase
Comments: From Achromobacter lyticus and Lysobacter enzymogenes. Digests bacterial cell walls. Type example of peptidase family M23.
References:
1.  Whitaker, D.R., Roy, C., Tsai, C.S. and Juraöek, L. Lytic enzymes of Sorangium sp. A comparison of the proteolytic properties of the α- and β-lytic proteases. Can. J. Biochem. 43 (1965) 1961–1970. [PMID: 5880182]
2.  Whitaker, D.R. and Roy, C. Concerning the nature of the α- and β-lytic proteases of Sorangium sp. Can. J. Biochem. 45 (1967) 911. [PMID: 6034704]
3.  Li, S. L., Norioka, S. and Sakiyama, F. Molecular cloning and nucleotide sequence of the β-lytic protease gene from Achromobacter lyticus. J. Bacteriol. 172 (1990) 6506–6511. [PMID: 2228973]
[EC 3.4.24.32 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.32]
 
 
EC 3.4.24.33     
Accepted name: peptidyl-Asp metalloendopeptidase
Reaction: Cleavage of Xaa┼Asp, Xaa┼Glu and Xaa┼cysteic acid bonds
Other name(s): endoproteinase Asp-N; peptidyl-Asp metalloproteinase
Comments: A metalloenzyme isolated from Pseudomonas fragi. Useful in protein sequencing applications because of its limited specificity. In peptidase family M72.
References:
1.  Porzio, M.A. and Pearson, A.M. Isolation of an extracellular neutral proteinase from Pseudomonas fragi. Biochim. Biophys. Acta 384 (1975) 235–241. [PMID: 236771]
2.  Drapeau, G.R. Substrate specificity of a proteolytic enzyme isolated from a mutant of Pseudomonas fragi. J. Biol. Chem. 255 (1980) 839–840. [PMID: 7188696]
3.  Ingrosso, D., Fowler, A.V., Bleibaum, J. and Clarke, S. Specificity of endoproteinase Asp-N (Pseudomonas fragi): cleavage at glutamyl residues in two proteins. Biochem. Biophys. Res. Commun. 162 (1989) 1528–1534. [PMID: 2669754]
[EC 3.4.24.33 created 1992]
 
 
EC 3.4.24.34     
Accepted name: neutrophil collagenase
Reaction: Cleavage of interstitial collagens in the triple helical domain. Unlike EC 3.4.24.7, interstitial collagenase, this enzyme cleaves type III collagen more slowly than type I
Other name(s): matrix metalloproteinase 8; PMNL collagenase; MMP-8
Comments: Similar to interstitial collagenase in specificity, but the product of a different gene and highly glycosylated. Stored in the specific granules of neutrophil leukocytes. In peptidase family M10 (interstitial collagenase family). Formerly included in EC 3.4.24.7
References:
1.  Hasty, K. A., Jeffrey, J. J., Hibbs, M. S. and Welgus, H. G. The collagen substrate specificity of human neutrophil collagenase. J. Biol. Chem. 262 (1987) 10048–10052. [PMID: 3038863]
2.  Hasty, K. A., Pourmotabbed, T. F., Goldberg, G. I., Thompson, J. P., Spinella, D. G., Stevens, R. M. and Mainardi, C. L. Human Neutrophil Collagenase. A distinct gene product with homology to other matrix metalloproteinases. J. Biol. Chem. 265 (1990) 11421–11424. [PMID: 2164002]
3.  Knäuper, V., Krämer, S., Reinke, H. and Tschesche, H. Characterization and activation of procollagenase from human polymorphonuclear leucocytes. N-terminal sequence and determination of the proenzyme and various proteolytically activated forms. Eur. J. Biochem. 189 (1990) 295–300. [PMID: 2159879]
[EC 3.4.24.34 created 1992]
 
 
EC 3.4.24.35     
Accepted name: gelatinase B
Reaction: Cleavage of gelatin types I and V and collagen types IV and V
Other name(s): 92-kDa gelatinase; matrix metalloproteinase 9; type V collagenase; 92-kDa type IV collagenase; macrophage gelatinase; 95 kDa type IV collagenase/gelatinase; collagenase IV (ambiguous); collagenase type IV (ambiguous); gelatinase MMP 9; MMP 9; type IV collagen metalloproteinase (ambiguous)
Comments: Similar to gelatinase A, but possesses a further domain . In peptidase family M10 (interstitial collagenase family)
References:
1.  Hibbs, M.S., Hoidal, J.R. and Kang, A.H. Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages. J. Clin. Invest. 80 (1987) 1644–1650. [PMID: 3680518]
2.  Wilhelm, S.M., Collier, I.E., Marmer, B.L., Eisen, A.Z., Grant, G.A. and Goldberg, G.I. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J. Biol. Chem. 264 (1989) 17213–17221. [PMID: 2551898]
3.  Mainardi, C. L. and Hasty, K. A. Secretion and glycosylation of rabbit macrophage type V collagenase. Matrix 10 (1990) 84–90. [PMID: 2165210]
[EC 3.4.24.35 created 1992]
 
 
EC 3.4.24.36     
Accepted name: leishmanolysin
Reaction: Preference for hydrophobic residues at P1 and P1′ and basic residues at P2′ and P3′. A model nonapeptide is cleaved at -Ala-Tyr┼Leu-Lys-Lys-
Other name(s): promastigote surface endopeptidase; glycoprotein gp63; Leishmania metalloproteinase; surface acid proteinase; promastigote surface protease
Comments: A membrane-bound glycoprotein found on the promastigote of various species of Leishmania protozoans. Contains consensus sequence for a zinc-binding site; Z-Tyr-Leu-NHOH is a strong inhibitor. The enzyme can activate its proenzyme by cleavage of the Val100┼Val bond. An acid pH optimum is found with certain protein substrates. Type example of peptidase family M8
References:
1.  Button, L.L. and McMaster, W.R. Molecular cloning of the major surface antigen of Leishmania. J. Exp. Med. 167 (1988) 724–729. [PMID: 3346625]
2.  Bouvier, J., Cordier, C., Vogel, H., Reichelt, R. and Etges, R. Characterization of the promastigote surface protease of Leishmania as a membrane-bound zinc endopeptidase. Mol. Biochem. Parasitol. 37 (1989) 235–246. [PMID: 2608099]
3.  Chaudhuri, G., Chaudhuri, M., Pan, A. and Chang, K.-P. Surface acid proteinase (gp63) of Leishmania mexicana. A metalloenzyme capable of protecting liposome-encapsulated proteins from phagolysosomal degradation by macrophages. J. Biol. Chem. 264 (1989) 7483–7489. [PMID: 2708373]
4.  Bouvier, J., Schneider, P., Etges, R. and Bordier, C. Peptide substrate specificity of the membrane-bound metalloprotease of Leishmania. Biochemistry 29 (1990) 10113–10119. [PMID: 2271643]
[EC 3.4.24.36 created 1992]
 
 
EC 3.4.24.37     
Accepted name: saccharolysin
Reaction: Cleavage of Pro┼Phe and Ala┼Ala bonds
Other name(s): proteinase yscD; yeast cysteine proteinase D (Misleading); Saccharomyces cerevisiae proteinase yscD
Comments: An 83 kDa cytoplasmic thiol-dependent metalloendopeptidase from Saccharomyces cerevisiae. In peptidase family M3 (thimet oligopeptidase family).
References:
1.  Achstetter, T., Ehmann, C. and Wolf, D.H. Proteinase yscD. Purification and characterization of a new yeast peptidase. J. Biol. Chem. 260 (1985) 4584–4590. [PMID: 3886641]
2.  Garcia-Alvarez, N., Teichert, U. and Wolf, D.H. Proteinase yscD mutants of yeast. Isolation and characterization. Eur. J. Biochem. 163 (1987) 339–346. [PMID: 3545833]
[EC 3.4.24.37 created 1989 as EC 3.4.22.22, transferred 1992 to EC 3.4.24.37]
 
 
EC 3.4.24.38     
Accepted name: gametolysin
Reaction: Cleavage of the proline- and hydroxyproline-rich proteins of the Chlamydomonas cell wall; also cleaves azocasein, gelatin and Leu-Trp-Met┼Arg-Phe-Ala
Other name(s): autolysin, Chlamydomonas cell wall degrading protease; lysin; Chlamydomonas reinhardtii metalloproteinase; gamete lytic enzyme; gamete autolysin
Comments: A glycoprotein found in the periplasmic space of Chlamydomonas reinhardtii gametes in a 62 kDa inactive form; decreased to 60 kDa upon activation. A zinc enzyme, inhibited by phosphoramidon, but also thiol activated. Type example of peptidase family M11
References:
1.  Jaenicke, L., Kunhe, W., Spessert, R., Wahle, U. and Waffenschmidt, S. Cell-wall lytic enzymes (autolysins) of Chlamydomonas reinhardtii are (hydroxy)proline-specific proteases. Eur. J. Biochem. 170 (1987) 485–491. [PMID: 3319620]
2.  Buchanan, M.J., Imam, S.H., Eskue, W.A. and Snell, W.J. Activation of the cell wall degrading protease, lysin, during sexual signalling in Chlamydomonas: the enzyme is stored as an inactive, higher relative molecular mass precursor in the periplasm. J. Cell. Biol. 108 (1989) 199–207. [PMID: 2910877]
3.  Matsuda, Y. Gametolysin. In: Barrett, A.J., Rawlings, N.D. & Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 1140–1143.
[EC 3.4.24.38 created 1992, modified 2000]
 
 
EC 3.4.24.39     
Accepted name: deuterolysin
Reaction: Preferential cleavage of bonds with hydrophobic residues in P1&prime
also Asn3┼Gln and Gly8┼Ser bonds in insulin B chain
Other name(s): Penicillium roqueforti protease II; microbial neutral proteinase II; acid metalloproteinase; neutral proteinase II; Penicillium roqueforti metalloproteinase
Comments: Proteolytic activity found in Penicillium roqueforti [4], P. caseicolum [4], Aspergillus sojae [3] and A. oryzae [1,5]. Optimum pH of 5 for digesting various proteins. Strong action on protamine and histones. Insensitive to phosphoramidon. About 20 kDa. A distinct Aspergillus sojae endopeptidase is larger and has a neutral pH optimum. Type example of peptidase family M35. Formerly included in EC 3.4.24.4
References:
1.  Nakadai, T., Nasuno, S. and Iguchi, N. Purification and properties of neutral proteinase II from Aspergillus oryzae. Agric. Biol. Chem. 37 (1973) 2703–2708.
2.  Gripon, J.-C. and Hermier, J. Le système protéolytique de Penicillium roqueforti. III. Purification, propriétés et spécificité d’une protéase inhibée par l’E.D.T.A. Biochimie 56 (1974) 1324–1332. [PMID: 4219726]
3.  Sekine, H. , Neutral proteinases I and II of Aspergillus sojae action on various substrates. Agric. Biol. Chem. 40 (1976) 703–709.
4.  Gripon, J.C., Auberger, B. and Lenoir, J. Metalloproteases from Penicillium caseicolum and P. roqueforti: comparision of specificity and chemical characterization. Int. J. Biochem. 12 (1980) 451–455. [PMID: 6998789]
5.  Vaganova, T.I., Ivanova, N.M. and Stepanov, V.M. Isolation and properties of the "acid" metalloproteinase from Aspergillus oryzae. Biochemistry (Mosc) 53 (1988) 1171–1178.
[EC 3.4.24.39 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.39]
 
 
EC 3.4.24.40     
Accepted name: serralysin
Reaction: Preferential cleavage of bonds with hydrophobic residues in P1′
Other name(s): Pseudomonas aeruginosa alkaline proteinase; Escherichia freundii proteinase; Serratia marcescens extracellular proteinase; Serratia marcescens metalloproteinase; Pseudomonas aeruginosa alk. protease; Serratia marcescens metalloprotease
Comments: A 50 kDa extracellular endopeptidase from Pseudomonas aeruginosa [1,2,6], Escherichia freundii [3], Serratia marcescens [4,5,6] and Erwinia chrysanthemi [7]. There is broad specificity in cleavage of the insulin B chain, with some species variations. The pH optimum for digesting various proteins is about 9 - 10. In peptidase family M10 (interstitial collagenase family). Formerly included in EC 3.4.24.4
References:
1.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [PMID: 4967801]
2.  Morihara, K., Tsuzuki, H. and Oka, T. On the specificity of Pseudomonas aeruginosa alkaline proteinase with synthetic peptides. Biochim. Biophys. Acta 309 (1973) 414–429. [PMID: 4199986]
3.  Nakajima, M., Mizusawa, K. and Yoshida, F. Purification and properties of an extracellular proteinase of psychrophilic Escherichia freundii. Eur. J. Biochem. 44 (1974) 87–96. [PMID: 4212288]
4.  Decedue, C.J., Broussard, E.A., II, L arson, A.D. and Braymer, H.D. Purification and characterization of the extracellular proteinase of Serratia marcescens. Biochim. Biophys. Acta 569 (1979) 293–301. [PMID: 383155]
5.  Doerr, M. and Traub, W.H. Purification and characterization of two Serratia marcescens proteases. Zentralbl. Bakteriol., Mikrobiol. Hyg. Ser. A 257 (1984) 6–19. [PMID: 6380155]
6.  Nakahama, K., Yoshimura, K., Marumoto, R., Kikuchi, M., Lee, I.S., Hase, T. and Matsubara, H. Cloning and sequencing of Serratia protease gene. Nucleic Acids Res. 14 (1986) 5843–5856. [PMID: 3016665]
7.  Dahler, G.S., Barras, F. and Keen, N.T. Cloning of genes encoding extracellular metalloproteases from Erwinia chrysanthemi EC16. J. Bacteriol. 172 (1990) 5803–5815. [PMID: 2211513]
8.  Okuda, K., Morihara, K., Atsumi, Y., Takeuchi, H., Kawamoto, S., Kawasaki, H., Suzuki, K. and Fukushima, J. Complete nucleotide sequence of the structural gene for alkaline proteinase from Pseudomonas aeruginosa IFO 3455. Infect. Immun. 58 (1990) 4083–4088. [PMID: 2123832]
[EC 3.4.24.40 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.40]
 
 
EC 3.4.24.41     
Accepted name: atrolysin B
Reaction: Cleavage of His5┼Leu, His10┼Leu, Ala14┼Leu, Tyr16┼Leu and Gly23┼Phe of insulin B chain; identical to the cleavage of insulin B chain by atrolysin C. Also cleaves ┼Ser bonds in glucagon
Other name(s): Crotalus atrox metalloendopeptidase b; hemorrhagic toxin b; Ht-b
Comments: From the venom of the western diamondback rattlesnake (Crotalus atrox). In peptidase family M12 (astacin family)
References:
1.  Bjarnason, J.B. and Tu, A.T. Hemorrhagic toxins from western diamondback rattlesnake (Crotalus atrox) venom: isolation and characterization of five toxins and the role of zinc in hemorrhagic toxin e. Biochemistry 17 (1978) 3395–3404. [PMID: 210790]
2.  Bjarnason, J.B., Hamilton, D. and Fox, J.W. Studies on the mechanism of hemorrhage production by five proteolytic hemorrhagic toxins from Crotalus atrox venom. Biol. Chem. Hoppe-Seyler 369 (1988) 121–129. [PMID: 3060135]
[EC 3.4.24.41 created 1992]
 
 
EC 3.4.24.42     
Accepted name: atrolysin C
Reaction: Cleavage of His5┼Leu, His10┼Leu, Ala14┼Leu, Tyr16┼Leu and Gly23┼Phe bonds in B chain of insulin. With small molecule substrates prefers hydrophobic residue at P2′ and small residue such as Ala, Gly at P1
Other name(s): Crotalus atrox metalloendopeptidase c; hemorrhagic toxin c and d
Comments: A 24 kDa hemorrhagic endopeptidase from the venom of the western diamondback rattlesnake (Crotalus atrox) that digests type IV collagen, and exists as two forms, c and d. Phosphoramidon inhibits in the 0.1 mM range. In peptidase family M12 (astacin family). Hemorrhagic toxin-2 of C. ruber ruber has the same Mr and specificity and is a homologue [4,6].
References:
1.  Bjarnason, J.B. and Tu, A.T. Hemorrhagic toxins from western diamondback rattlesnake (Crotalus atrox) venom: isolation and characterization of five toxins and the role of zinc in hemorrhagic toxin e. Biochemistry 17 (1978) 3395–3404. [PMID: 210790]
2.  Fox, J.W., Campbell, R., Beggerly, L. and Bjarnason, J.B. Substrate specificities and inhibition of two hemorrhagic zinc proteases Ht-c and Ht-d from Crotalus atrox venom. Eur. J. Biochem. 156 (1986) 65–72. [PMID: 3514216]
3.  Bjarnason, J.B. and Fox, J.W. Characterization of two hemorrhagic zinc proteinases, toxin c and toxin d, from western diamondback rattlesnake (Crotalus atrox) venom. Biochim. Biophys. Acta 911 (1987) 356–363. [PMID: 3101740]
4.  Mori, N., Nikai, T., Sugihara, H. and Tu, A.T. Biochemical characterization of hemorrhagic toxins with fibrinogenase activity isolated from Crotalus ruber ruber venom. Arch. Biochem. Biophys. 253 (1987) 108–121. [PMID: 2949699]
5.  Shannon, J.D., Baramova, E.N., Bjarnason, J.B. and Fox, F.W. Amino acid sequence of a Crotalus atrox venom metalloproteinase which cleaves type IV collagen and gelatin. J. Biol. Chem. 264 (1989) 11575–11583. [PMID: 2745407]
6.  Takeya, H., Onikura, A., Nikai, T., Sugihara, H. and Iwanaga, S. Primary structure of a hemorrhagic metalloproteinase, HT- 2, isolated from the venom of Crotalus ruber ruber. J. Biochem. (Tokyo) 108 (1990) 711–719. [PMID: 2081731]
[EC 3.4.24.42 created 1992]
 
 
EC 3.4.24.43     
Accepted name: atroxase
Reaction: Cleavage of His5┼Leu, Ser9┼His, His10┼Leu, Ala14┼Leu and Tyr16┼Leu of insulin B chain
Comments: A nonhemorrhagic endopeptidase from the venom of the western diamondback rattlesnake (Crotalus atrox) that cleaves fibrinogen. In peptidase family M12 (astacin family)
References:
1.  Willis, T.W. and Tu, A.T. Purification and biochemical characterization of atroxase, a nonhemorrhagic fibrinolytic protease from western diamondback rattlesnake venom. Biochemistry 27 (1988) 4769–4777. [PMID: 3167016]
[EC 3.4.24.43 created 1992]
 
 
EC 3.4.24.44     
Accepted name: atrolysin E
Reaction: Cleavage of Asn3┼Gln, Ser9┼His and Ala14┼Leu bonds in insulin B chain and Tyr14┼Gln and Thr8┼Ser in A chain. Cleaves type IV collagen at Ala73┼Gln in α1(IV) and at Gly7┼Leu in α2(IV)
Other name(s): Crotalus atrox metalloendopeptidase e; hemorrhagic toxin e
Comments: A 25.7 kDa hemorrhagic endopeptidase from the venom of the western diamondback rattlesnake (Crotalus atrox) that digests basement membrane components, including the triple helix of type IV collagen. Such action is believed to contribute to the hemorrhagic property by weakening capillary walls. In peptidase family M12 (astacin family)
References:
1.  Bjarnason, J.B. and Tu, A.T. Hemorrhagic toxins from western diamondback rattlesnake (Crotalus atrox) venom: isolation and characterization of five toxins and the role of zinc in hemorrhagic toxin e. Biochemistry 17 (1978) 3395–3404. [PMID: 210790]
2.  Bjarnason, J.B. and Fox, J.W. Proteolytic specificity and cobalt exchange of hemorrhagic toxin e, a zinc protease isolated from the venom of the western diamondback rattlesnake (Crotalus atrox). Biochemistry 22 (1983) 3770–3778. [PMID: 6351911]
3.  Baramova, E.N., Shannon, J.D., Bjarnason, J.B. and Fox, J.W. Identification of the cleavave sites by a hemorrhagic metalloproteinase in type IV collagen. Matrix 10 (1990) 91–97. [PMID: 2374521]
[EC 3.4.24.44 created 1992]
 
 
EC 3.4.24.45     
Accepted name: atrolysin F
Reaction: Cleavage of Val2┼Asn, Gln4┼His, Leu6┼Cys, His10┼Leu, Ala14┼Leu and Tyr16┼Leu bonds in insulin B chain
Other name(s): Crotalus atrox metalloendopeptidase; hemorrhagic toxin f; Crotalus atrox metalloendopeptidase f
Comments: A 64 kDa hemorrhagic endopeptidase from the venom of the western diamondback rattlesnake (Crotalus atrox) that digests the γ chain of fibrinogen. Immunologically distinct from EC 3.4.24.1, atrolysin A.
References:
1.  Nikai, T., Mori, N., Kishida, M., Sugihara, H. and Tu, A.T. Isolation and biochemical characterization of hemorrhagic toxin f from the venom of Crotalus atrox (western diamondback rattlesnake). Arch. Biochem. Biophys. 231 (1984) 309–319. [PMID: 6375570]
[EC 3.4.24.45 created 1992]
 
 
EC 3.4.24.46     
Accepted name: adamalysin
Reaction: Cleavage of Phe1┼Val, His5┼Leu, His10┼Leu, Ala14┼Leu, Leu15┼Tyr, and Tyr16┼Leu of insulin B chain
Other name(s): Crotalus adamanteus metalloendopeptidase; proteinase I and II; Crotalus adamanteus venom proteinase II; adamalysin II
Comments: From the venom of the eastern diamondback rattlesnake (Crotalus adamanteus). Two isoenzymes of approx. 24 kDa that inactivate α1-proteinase inhibitor by a single cleavage. In peptidase family M12 (astacin family)
References:
1.  Kurecki, T., Laskowski, M., Sr. and Kress, L.F. Purification and some properties of two proteinases from Crotalus adamanteus venom that inactivate human α1-proteinase inhibitor. J. Biol. Chem. 253 (1978) 8340–8345. [PMID: 309470]
[EC 3.4.24.46 created 1992]
 
 
EC 3.4.24.47     
Accepted name: horrilysin
Reaction: Cleavage of only the single bond Ala14┼Leu in the insulin B chain, Ser12┼Leu in the A chain, and Ile┼Gly, Pro┼Ala, and Ser┼Trp in melittin
Other name(s): Crotalus horridus metalloendopeptidase; hemorrhagic proteinase IV; Crotalus horridus horridus venom hemorrhagic proteinase
Comments: A 56 kDa hemorrhagic endopeptidase from the venom of the timber rattlesnake (Crotalus horridus horridus) that cleaves basement membrane, hide powder and fibrinogen.
References:
1.  Civello, D.J., Duong, H.L. and Geren, C.R. Isolation and characterization of a hemorrhagic proteinase from timber rattlesnake venom. Biochemistry 22 (1983) 749–755. [PMID: 6340728]
2.  Civello, D.J., Moran, J.B. and Geren, C.R. Substrate specificity of a hemorrhagic proteinase from timber rattlesnake venom. Biochemistry 22 (1983) 755–762. [PMID: 6340729]
[EC 3.4.24.47 created 1992]
 
 
EC 3.4.24.48     
Accepted name: ruberlysin
Reaction: Cleavage of His10┼Leu, Ala14┼Leu, Tyr16┼Leu and Gly23┼Phe bonds in the B chain of insulin; His┼Pro, Pro┼Phe, and Trp┼Ser of angiotensin I; and Gly┼Phe of Met enkephalin
Other name(s): Crotalus ruber metalloendopeptidase II; hemorrhagic toxin II
Comments: A 25 kDa hemorrhagic endopeptidase from the venom of the red rattlesnake (Crotalus ruber ruber) that cleaves fibrinogen. In peptidase family M12 (astacin family)
References:
1.  Mori, N., Nikai, T., Sugihara, H. and Tu, A.T. Biochemical characterization of hemorrhagic toxins with fibrinogenase activity isolated from Crotalus ruber ruber venom. Arch. Biochem. Biophys. 253 (1987) 108–121. [PMID: 2949699]
2.  Takeya, H., Onikura, A., Nikai, T., Sugihara, H. and Iwanaga, S. Primary structure of a hemorrhagic metalloproteinase, HT- 2, isolated from the venom of Crotalus ruber ruber. J. Biochem. (Tokyo) 108 (1990) 711–719. [PMID: 2081731]
[EC 3.4.24.48 created 1992]
 
 
EC 3.4.24.49     
Accepted name: bothropasin
Reaction: Cleavage of His5┼Leu, His10┼Leu, Ala14┼Leu, Tyr16┼Leu and Phe24┼Phe in insulin B chain
Other name(s): Bothrops jararaca venom metalloproteinase
Comments: Caseinolytic endopeptidase of jararaca snake (Bothrops jararaca) venom; 48 kDa. In peptidase family M12
References:
1.  Mandelbaum, F.J., Reichel, A.P. and Assakura, M.T. Isolation and characterization of a proteolytic enzyme from the venom of the snake Bothrops jararaca (jararaca). Toxicon 20 (1982) 955–972. [PMID: 6819660]
[EC 3.4.24.49 created 1992]
 
 
EC 3.4.24.50     
Accepted name: bothrolysin
Reaction: Cleavage of Gln4┼His, Ser9┼His and Ala14┼Leu of insulin B chain and Pro┼Phe of angiotensin I
Other name(s): Bothrops metalloendopeptidase J; J protease
Comments: A 22.5 kDa endopeptidase from the venom of the jararaca snake (Bothrops jararaca), insensitive to phosphoramidon at 0.5 mM. In peptidase family M12 (astacin family)
References:
1.  Tanizaki, M.M., Zingali, R.B., Kawazaki, H., Imajoh, S., Yamazaki, S. and Suzuki, K. Purification and some characteristics of a zinc metalloprotease from the venom of Bothrops jararaca (jararaca). Toxicon 27 (1989) 747–755. [PMID: 2781574]
[EC 3.4.24.50 created 1992]
 
 
EC 3.4.24.51     
Accepted name: ophiolysin
Reaction: Cleavage of Asn3┼Gln, Gln4┼His, His10┼Leu, Ala14┼Leu, and Tyr16┼Leu in insulin B chain
Other name(s): Ophiophagus metalloendopeptidase