The Enzyme Database

Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB)

Proposed Changes to the Enzyme List

The entries below are proposed additions and amendments to the Enzyme Nomenclature list. They were prepared for the NC-IUBMB by Kristian Axelsen, Richard Cammack, Ron Caspi, Masaaki Kotera, Andrew McDonald, Gerry Moss, Dietmar Schomburg, Ida Schomburg and Keith Tipton. Comments and suggestions on these draft entries should be sent to Dr Andrew McDonald (Department of Biochemistry, Trinity College Dublin, Dublin 2, Ireland). The date on which an enzyme will be made official is appended after the EC number. To prevent confusion please do not quote new EC numbers until they are incorporated into the main list.

An asterisk before 'EC' indicates that this is an amendment to an existing enzyme rather than a new enzyme entry.


Contents

EC 1.1.1.291 2-hydroxymethylglutarate dehydrogenase
*EC 1.1.3.8 L-gulonolactone oxidase
EC 1.1.3.24 transferred
EC 1.1.99.31 (S)-mandelate dehydrogenase
*EC 1.3.2.3 L-galactonolactone dehydrogenase
EC 1.3.3.12 L-galactonolactone oxidase
*EC 1.7.3.1 nitroalkane oxidase
*EC 1.13.11.32 2-nitropropane dioxygenase
EC 2.7.7.64 UTP-monosaccharide-1-phosphate uridylyltransferase
EC 2.7.8.27 sphingomyelin synthase
EC 3.4.13.22 D-Ala-D-Ala dipeptidase
*EC 3.4.22.36 caspase-1
EC 3.4.22.55 caspase-2
EC 3.4.22.56 caspase-3
EC 3.4.22.57 caspase-4
EC 3.4.22.58 caspase-5
EC 3.4.22.59 caspase-6
EC 3.4.22.60 caspase-7
EC 3.4.22.61 caspase-8
EC 3.4.22.62 caspase-9
EC 3.4.22.63 caspase-10
EC 3.4.22.64 caspase-11
EC 3.5.2.18 enamidase
EC 4.2.1.110 aldos-2-ulose dehydratase
EC 4.2.1.111 1,5-anhydro-D-fructose dehydratase
EC 5.3.3.15 ascopyrone tautomerase
EC 6.3.1.12 D-aspartate ligase
EC 6.4.1.7 2-oxoglutarate carboxylase


EC 1.1.1.291
Accepted name: 2-hydroxymethylglutarate dehydrogenase
Reaction: (S)-2-hydroxymethylglutarate + NAD+ = 2-formylglutarate + NADH + H+
For diagram of nicotinate catabolism, click here
Other name(s): HgD
Systematic name: (S)-2-hydroxymethylglutarate:NAD+ oxidoreductase
Comments: NADP+ cannot replace NAD+. Forms part of the nicotinate-fermentation catabolism pathway in Eubacterium barkeri. Other enzymes involved in this pathway are EC 1.17.1.5 (nicotinate dehydrogenase), EC 1.3.7.1 (6-hydroxynicotinate reductase), EC 3.5.2.18 (enamidase), EC 5.4.99.4 (2-methyleneglutarate mutase), EC 5.3.3.6 (methylitaconate Δ-isomerase), EC 4.2.1.85 (dimethylmaleate hydratase) and EC 4.1.3.32 (2,3-dimethylmalate lyase).
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, CAS registry number: 1073478-76-8
References:
1.  Alhapel, A., Darley, D.J., Wagener, N., Eckel, E., Elsner, N. and Pierik, A.J. Molecular and functional analysis of nicotinate catabolism in Eubacterium barkeri. Proc. Natl. Acad. Sci. USA 103 (2006) 12341–12346. [PMID: 16894175]
[EC 1.1.1.291 created 2006]
 
 
*EC 1.1.3.8
Accepted name: L-gulonolactone oxidase
Reaction: L-gulono-1,4-lactone + O2 = L-ascorbate + H2O2 (overall reaction)
(1a) L-gulono-1,4-lactone + O2 = L-xylo-hex-2-ulono-1,4-lactone + H2O2
(1b) L-xylo-hex-2-ulono-1,4-lactone = L-ascorbate (spontaneous)
For diagram of mammalian ascorbic acid biosynthesis, click here
Other name(s): L-gulono-γ-lactone: O2 oxidoreductase; L-gulono-γ-lactone oxidase; L-gulono-γ-lactone:oxidoreductase; GLO
Systematic name: L-gulono-1,4-lactone:oxygen 3-oxidoreductase
Comments: A microsomal flavoprotein (FAD). The product spontaneously isomerizes to L-ascorbate. While most higher animals can synthesize asborbic acid, primates and guinea pigs cannot [3].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 9028-78-8
References:
1.  Isherwood, F.A., Mapson, L.W. and Chen, Y.T. Synthesis of L-ascorbic acid in rat liver homogenates. Conversion of L-gulono- and L-galactono-γ-lactone and the respective acids into L-ascorbic acid. Biochem. J. 76 (1960) 157–171. [PMID: 14405898]
2.  Kiuchi, K., Noshikimi, M. and Yagi, K. Purification and characterization of L-gulonolactone oxidase from chicken kidney microsomes. Biochemistry 21 (1982) 5076–5082. [PMID: 7138847]
3.  Nishikimi, M., Fukuyama, R., Minoshima, S., Shimizu, N. and Yagi, K. Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-γ-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man. J. Biol. Chem. 269 (1994) 13685–13688. [PMID: 8175804]
4.  Chatterjee, I.B., Chatterjee, G.C., Ghosh, N.C. and Guha, B.C. Identification of 2-keto-L-gulonolactone as an intermediate in the biosynthesis of L-ascorbic acid. Naturwissenschaften 46 (1959) 475.
[EC 1.1.3.8 created 1965, modified 2001, modified 2006]
 
 
EC 1.1.3.24
Transferred entry: L-galactonolactone oxidase. Now EC 1.3.3.12, L-galactonolactone oxidase. The enzyme had been incorrectly classified as acting upon a CH-OH donor rather than a CH-CH donor
[EC 1.1.3.24 created 1984, deleted 2006]
 
 
EC 1.1.99.31
Accepted name: (S)-mandelate dehydrogenase
Reaction: (S)-mandelate + acceptor = phenylglyoxylate + reduced acceptor
For diagram of reaction, click here
Glossary: (S)-mandelate = (S)-2-hydroxy-2-phenylacetate
phenylglyoxylate = benzoylformate = 2-oxo-2-phenylacetate
Other name(s): MDH
Systematic name: (S)-mandelate:acceptor 2-oxidoreductase
Comments: This enzyme is a member of the FMN-dependent α-hydroxy-acid oxidase/dehydrogenase family [1]. While all enzymes of this family oxidize the (S)-enantiomer of an α-hydroxy acid to an α-oxo acid, the ultimate oxidant (oxygen, intramolecular heme or some other acceptor) depends on the particular enzyme. This enzyme transfers the electron pair from FMNH2 to a component of the electron transport chain, most probably ubiquinone [1,2]. It is part of a metabolic pathway in Pseudomonads that allows these organisms to utilize mandelic acid, derivatized from the common soil metabolite amygdalin, as the sole source of carbon and energy [2]. The enzyme has a large active-site pocket and preferentially binds substrates with longer sidechains, e.g. 2-hydroxyoctanoate rather than 2-hydroxybutyrate [1]. It also prefers substrates that, like (S)-mandelate, have β unsaturation, e.g. (indol-3-yl)glycolate compared with (indol-3-yl)lactate [1]. Esters of mandelate, such as methyl (S)-mandelate, are also substrates [3].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, UM-BBD, CAS registry number: 9067-95-2
References:
1.  Lehoux, I.E. and Mitra, B. (S)-Mandelate dehydrogenase from Pseudomonas putida: mechanistic studies with alternate substrates and pH and kinetic isotope effects. Biochemistry 38 (1999) 5836–5848. [PMID: 10231535]
2.  Dewanti, A.R., Xu, Y. and Mitra, B. Role of glycine 81 in (S)-mandelate dehydrogenase from Pseudomonas putida in substrate specificity and oxidase activity. Biochemistry 43 (2004) 10692–10700. [PMID: 15311930]
3.  Dewanti, A.R., Xu, Y. and Mitra, B. Esters of mandelic acid as substrates for (S)-mandelate dehydrogenase from Pseudomonas putida: implications for the reaction mechanism. Biochemistry 43 (2004) 1883–1890. [PMID: 14967029]
[EC 1.1.99.31 created 2006]
 
 
*EC 1.3.2.3
Accepted name: L-galactonolactone dehydrogenase
Reaction: L-galactono-1,4-lactone + 4 ferricytochrome c = L-dehydroascorbate + 4 ferrocytochrome c + 4 H+ (overall reaction)
(1a) L-galactono-1,4-lactone + 2 ferricytochrome c = L-ascorbate + 2 ferrocytochrome c + 2 H+
(1b) L-ascorbate + 2 ferricytochrome c = L-dehydroascorbate + 2 ferrocytochrome c + 2 H+ (spontaneous)
Other name(s): galactonolactone dehydrogenase; L-galactono-γ-lactone dehydrogenase; L-galactono-γ-lactone:ferricytochrome-c oxidoreductase; GLDHase; GLDase
Systematic name: L-galactono-1,4-lactone:ferricytochrome-c oxidoreductase
Comments: This enzyme catalyses the final step in the biosynthesis of L-ascorbic acid in higher plants and in nearly all higher animals with the exception of primates and some birds [5]. The enzyme is very specific for its substrate L-galactono-1,4-lactone as D-galactono-γ-lactone, D-gulono-γ-lactone, L-gulono-γ-lactone, D-erythronic-γ-lactone, D-xylonic-γ-lactone, L-mannono-γ-lactone, D-galactonate, D-glucuronate and D-gluconate are not substrates [5]. FAD, NAD+, NADP+ and O2 (cf. EC 1.3.3.12, L-galactonolactone oxidase) cannot act as electron acceptor [5].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 9029-02-1
References:
1.  Mapson, L.W. and Breslow, E. Properties of partially purified L-galactono-γ-lactone dehydrogenase. Biochem. J. 65 (1957) 29.
2.  Mapson, L.W., Isherwood, F.A. and Chen, Y.T. Biological synthesis of L-ascorbic acid: the conversion of L-galactono-γ-lactone into L-ascorbic acid by plant mitochondria. Biochem. J. 56 (1954) 21–28. [PMID: 13126087]
3.  Isherwood, F.A., Chen, Y.T. and Mapson, L.W. Synthesis of L-ascorbic acid in plants and animals. Biochem. J. 56 (1954) 1–15. [PMID: 13126085]
4.  Ôba, K., Ishikawa, S., Nishikawa, M., Mizuno, H. and Yamamoto, T. Purification and properties of L-galactono-γ-lactone dehydrogenase, a key enzyme for ascorbic acid biosynthesis, from sweet potato roots. J. Biochem. (Tokyo) 117 (1995) 120–124. [PMID: 7775377]
5.  Østergaard, J., Persiau, G., Davey, M.W., Bauw, G. and Van Montagu, M. Isolation of a cDNA coding for L-galactono-γ-lactone dehydrogenase, an enzyme involved in the biosynthesis of ascorbic acid in plants. Purification, characterization, cDNA cloning, and expression in yeast. J. Biol. Chem. 272 (1997) 30009–30016. [PMID: 9374475]
[EC 1.3.2.3 created 1961, modified 2006]
 
 
EC 1.3.3.12
Accepted name: L-galactonolactone oxidase
Reaction: L-galactono-1,4-lactone + O2 = L-ascorbate + H2O2
Other name(s): L-galactono-1,4-lactone oxidase
Systematic name: L-galactono-1,4-lactone:oxygen 3-oxidoreductase
Comments: A flavoprotein. Acts on the 1,4-lactones of L-galactonic, D-altronic, L-fuconic, D-arabinic and D-threonic acids; not identical with EC 1.1.3.8 L-gulonolactone oxidase. (cf. EC 1.3.2.3 galactonolactone dehydrogenase).
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 69403-13-0
References:
1.  Bleeg, H.S. and Christensen, F. Biosynthesis of ascorbate in yeast. Purification of L-galactono-1,4-lactone oxidase with properties different from mammalian L-gulonolactone oxidase. Eur. J. Biochem. 127 (1982) 391–396. [PMID: 6754380]
[EC 1.3.3.12 created 1984 as EC 1.1.3.24, transferred 2006 to EC 1.3.3.12]
 
 
*EC 1.7.3.1
Accepted name: nitroalkane oxidase
Reaction: a nitroalkane + H2O + O2 = an aldehyde or ketone + nitrite + H2O2
Other name(s): nitroethane oxidase; NAO; nitroethane:oxygen oxidoreductase
Systematic name: nitroalkane:oxygen oxidoreductase
Comments: Has an absolute requirement for FAD [4]. While nitroethane may be the physiological substrate [2], the enzyme also acts on several other nitroalkanes, including 1-nitropropane, 2-nitropropane, 1-nitrobutane, 1-nitropentane, 1-nitrohexane, nitrocyclohexane and some nitroalkanols [4]. Differs from EC 1.13.11.16, nitronate monooxygenase, in that the preferred substrates are neutral nitroalkanes rather than anionic nitronates [4].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, UM-BBD, CAS registry number: 9029-36-1, 65802-82-6
References:
1.  Little, H.N. Oxidation of nitroethane by extracts from Neurospora. J. Biol. Chem. 193 (1951) 347–358. [PMID: 14907722]
2.  Kido, T., Hashizume, K. and Soda, K. Purification and properties of nitroalkane oxidase from Fusarium oxysporum. J. Bacteriol. 133 (1978) 53–58. [PMID: 22538]
3.  Daubner, S.C., Gadda, G., Valley, M.P. and Fitzpatrick, P.F. Cloning of nitroalkane oxidase from Fusarium oxysporum identifies a new member of the acyl-CoA dehydrogenase superfamily. Proc. Natl. Acad. Sci. USA 99 (2002) 2702–2707. [PMID: 11867731]
4.  Fitzpatrick, P.F., Orville, A.M., Nagpal, A. and Valley, M.P. Nitroalkane oxidase, a carbanion-forming flavoprotein homologous to acyl-CoA dehydrogenase. Arch. Biochem. Biophys. 433 (2005) 157–165. [PMID: 15581574]
5.  Valley, M.P., Tichy, S.E. and Fitzpatrick, P.F. Establishing the kinetic competency of the cationic imine intermediate in nitroalkane oxidase. J. Am. Chem. Soc. 127 (2005) 2062–2066. [PMID: 15713081]
[EC 1.7.3.1 created 1961, modified 2006, modified 2009]
 
 
*EC 1.13.11.32
Transferred entry: 2-nitropropane dioxygenase. Now EC 1.13.12.16, nitronate monooxygenase
[EC 1.13.11.32 created 1984, modified 2006, deleted 2009]
 
 
EC 2.7.7.64
Accepted name: UTP-monosaccharide-1-phosphate uridylyltransferase
Reaction: UTP + a monosaccharide 1-phosphate = diphosphate + UDP-monosaccharide
Glossary: UDP-Xyl = UDP-α-D-xylose
UDP-L-Ara = UDP-β-L-arabinopyranose
Other name(s): UDP-sugar pyrophosphorylase; PsUSP
Comments: Requires Mg2+ or Mn2+ for maximal activity. The reaction can occur in either direction and it has been postulated that MgUTP and Mg-diphosphate are the actual substrates [1,2]. The enzyme catalyses the formation of UDP-Glc, UDP-Gal, UDP-GlcA, UDP-L-Ara and UDP-Xyl, showing broad substrate specificity towards monosaccharide 1-phosphates. Mannose 1-phosphate, L-Fucose 1-phosphate and glucose 6-phosphate are not substrates and UTP cannot be replaced by other nucleotide triphosphates [1].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG
References:
1.  Kotake, T., Yamaguchi, D., Ohzono, H., Hojo, S., Kaneko, S., Ishida, H.K. and Tsumuraya, Y. UDP-sugar pyrophosphorylase with broad substrate specificity toward various monosaccharide 1-phosphates from pea sprouts. J. Biol. Chem. 279 (2004) 45728–45736. [PMID: 15326166]
2.  Rudick, V.L. and Weisman, R.A. Uridine diphosphate glucose pyrophosphorylase of Acanthamoeba castellanii. Purification, kinetic, and developmental studies. J. Biol. Chem. 249 (1974) 7832–7840. [PMID: 4430676]
[EC 2.7.7.64 created 2006]
 
 
EC 2.7.8.27
Accepted name: sphingomyelin synthase
Reaction: a ceramide + a phosphatidylcholine = a sphingomyelin + a 1,2-diacyl-sn-glycerol
For diagram of reaction, click here
Glossary: sphingomyelin = a ceramide-1-phosphocholine
ceramide = an N-acylsphingoid. The fatty acids of naturally occurring ceramides range in chain length from about C16 to about C26 and may contain one or more double bonds and/or hydroxy substituents at C-2
sphingoid = sphinganine, i.e. D-erythro-2-aminooctadecane-1,3-diol, and its homologues and stereoisomers (see also Lip-1.4)
Other name(s): SM synthase; SMS1; SMS2
Systematic name: ceramide:phosphatidylcholine cholinephosphotransferase
Comments: The reaction can occur in both directions [3]. This enzyme occupies a central position in sphingolipid and glycerophospholipid metabolism [4]. Up- and down-regulation of its activity has been linked to mitogenic and pro-apoptotic signalling in a variety of mammalian cell types [4]. Unlike EC 2.7.8.3, ceramide cholinephosphotransferase, CDP-choline cannot replace phosphatidylcholine as the donor of the phosphocholine moiety of sphingomyelin [2].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, CAS registry number: 58703-97-2
References:
1.  Ullman, M.D. and Radin, N.S. The enzymatic formation of sphingomyelin from ceramide and lecithin in mouse liver. J. Biol. Chem. 249 (1974) 1506–1512. [PMID: 4817756]
2.  Voelker, D.R. and Kennedy, E.P. Cellular and enzymic synthesis of sphingomyelin. Biochemistry 21 (1982) 2753–2759. [PMID: 7093220]
3.  Huitema, K., van den Dikkenberg, J., Brouwers, J.F. and Holthuis, J.C. Identification of a family of animal sphingomyelin synthases. EMBO J. 23 (2004) 33–44. [PMID: 14685263]
4.  Tafesse, F.G., Ternes, P. and Holthuis, J.C. The multigenic sphingomyelin synthase family. J. Biol. Chem. 281 (2006) 29421–29425. [PMID: 16905542]
5.  Yamaoka, S., Miyaji, M., Kitano, T., Umehara, H. and Okazaki, T. Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells. J. Biol. Chem. 279 (2004) 18688–18693. [PMID: 14976195]
[EC 2.7.8.27 created 2006]
 
 
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB
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 3.4.22.36
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, MEROPS, PDB, CAS registry number: 122191-40-6
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 3.4.22.55
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 182372-14-1
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, CAS registry number: 169592-56-7
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 182762-08-9
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 192465-11-5
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 182372-15-2
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, CAS registry number: 189258-14-8
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, CAS registry number: 179241-78-2
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB, CAS registry number: 180189-96-2
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 189088-85-5
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.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG
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 3.5.2.18
Accepted name: enamidase
Reaction: 6-oxo-1,4,5,6-tetrahydronicotinate + 2 H2O = 2-formylglutarate + NH3
For diagram of nicotinate catabolism, click here
Systematic name: 6-oxo-1,4,5,6-tetrahydronicotinate amidohydrolase
Comments: Contains iron and Zn2+. Forms part of the nicotinate-fermentation catabolism pathway in Eubacterium barkeri. Other enzymes involved in this pathway are EC 1.17.1.5 (nicotinate dehydrogenase), EC 1.3.7.1 (6-hydroxynicotinate reductase), EC 1.1.1.291 (2-hydroxymethylglutarate dehydrogenase), EC 5.4.99.4 (2-methyleneglutarate mutase), EC 5.3.3.6 (methylitaconate Δ-isomerase), EC 4.2.1.85 (dimethylmaleate hydratase) and EC 4.1.3.32 (2,3-dimethylmalate lyase).
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, PDB
References:
1.  Alhapel, A., Darley, D.J., Wagener, N., Eckel, E., Elsner, N. and Pierik, A.J. Molecular and functional analysis of nicotinate catabolism in Eubacterium barkeri. Proc. Natl. Acad. Sci. USA 103 (2006) 12341–12346. [PMID: 16894175]
[EC 3.5.2.18 created 2006]
 
 
EC 4.2.1.110
Accepted name: aldos-2-ulose dehydratase
Reaction: 1,5-anhydro-D-fructose = 2-hydroxy-2-(hydroxymethyl)-2H-pyran-3(6H)-one + H2O (overall reaction)
(1a) 1,5-anhydro-D-fructose = 1,5-anhydro-4-deoxy-D-glycero-hex-3-en-2-ulose + H2O
(1b) 1,5-anhydro-4-deoxy-D-glycero-hex-3-en-2-ulose = 2-hydroxy-2-(hydroxymethyl)-2H-pyran-3(6H)-one
For diagram of the anhydrofructose pathway, click here
Glossary: 1,5-anhydro-D-fructose = 1,5-anhydro-D-arabino-hex-2-ulose = (4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)dihydro-2H-pyran-3(4H)-one
ascopyrone M = 1,5-anhydro-4-deoxy-D-glycero-hex-3-en-2-ulose = (6S)-4-hydroxy-6-(hydroxymethyl)-2H-pyran-3(6H)-one
microthecin = 2-hydroxy-2-(hydroxymethyl)-2H-pyran-3(6H)-one
Other name(s): pyranosone dehydratase; AUDH; 1,5-anhydro-D-fructose dehydratase (microthecin-forming)
Systematic name: 1,5-anhydro-D-fructose hydro-lyase (microthecin-forming)
Comments: This enzyme catalyses two of the steps in the anhydrofructose pathway, which leads to the degradation of glycogen and starch via 1,5-anhydro-D-fructose [1,2]. Aldose-2-uloses such as 2-dehydroglucose can also act as substrates, but more slowly [1,2,4]. This is a bifunctional enzyme that acts as both a lyase and as an isomerase [2]. Differs from EC 4.2.1.111, which can carry out only reaction (1a), is inhibited by its product and requires metal ions for activity [1].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, UM-BBD, CAS registry number: 101920-80-3
References:
1.  Yu, S. and Fiskesund, R. The anhydrofructose pathway and its possible role in stress response and signaling. Biochim. Biophys. Acta 1760 (2006) 1314–1322. [PMID: 16822618]
2.  Yu, S. Enzymatic description of the anhydrofructose pathway of glycogen degradation. II. Gene identification and characterization of the reactions catalyzed by aldos-2-ulose dehydratase that converts 1,5-anhydro-D-fructose to microthecin with ascopyrone M as the intermediate. Biochim. Biophys. Acta 1723 (2005) 63–73. [PMID: 15716041]
3.  Broberg, A., Kenne, L. and Pedersén, M. Presence of microthecin in the red alga Gracilariopsis lemaneiformis and its formation from 1,5-anhydro-D-fructose. Phytochemistry 41 (1996) 151–154.
4.  Gabriel, J., Volc, J., Sedmera, P., Daniel, G. and Kubátová, E. Pyranosone dehydratase from the basidiomycete Phanerochaete chrysosporium: improved purification, and identification of 6-deoxy-D-glucosone and D-xylosone reaction products. Arch. Microbiol. 160 (1993) 27–34. [PMID: 8352649]
5.  Yu, S., Refdahl, C. and Lundt, I. Enzymatic description of the anhydrofructose pathway of glycogen degradation; I. Identification and purification of anhydrofructose dehydratase, ascopyrone tautomerase and α-1,4-glucan lyase in the fungus Anthracobia melaloma. Biochim. Biophys. Acta 1672 (2004) 120–129. [PMID: 15110094]
[EC 4.2.1.110 created 2006]
 
 
EC 4.2.1.111
Accepted name: 1,5-anhydro-D-fructose dehydratase
Reaction: 1,5-anhydro-D-fructose = 1,5-anhydro-4-deoxy-D-glycero-hex-3-en-2-ulose + H2O
For diagram of the anhydrofructose pathway, click here
Glossary: 1,5-anhydro-D-fructose = 1,5-anhydro-D-arabino-hex-2-ulose = (4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)dihydro-2H-pyran-3(4H)-one
ascopyrone M = 1,5-anhydro-4-deoxy-D-glycero-hex-3-en-2-ulose = (6S)-4-hydroxy-6-(hydroxymethyl)-2H-pyran-3(6H)-one
Other name(s): 1,5-anhydro-D-fructose 4-dehydratase; 1,5-anhydro-D-fructose hydrolyase; 1,5-anhydro-D-arabino-hex-2-ulose dehydratase; AFDH; AF dehydratase; 1,5-anhydro-D-fructose hydro-lyase
Systematic name: 1,5-anhydro-D-fructose hydro-lyase (ascopyrone-M-forming)
Comments: This enzyme catalyses one of the steps in the anhydrofructose pathway, which leads to the degradation of glycogen and starch via 1,5-anhydro-D-fructose [1,2]. The other enzymes involved in this pathway are EC 4.2.1.110 (aldos-2-ulose dehydratase), EC 4.2.2.13 [exo-(1→4)-α-D-glucan lyase] and EC 5.3.2.7 (ascopyrone tautomerase). Requires divalent (Ca2+ or Mg2+) or monovalent cations (Na+) for optimal activity. Unlike EC 4.2.1.110, the enzyme is specific for 1,5-anhydro-D-fructose as substrate and shows no activity towards aldose-2-uloses such as 2-dehydroglucose [1,2,3]. In addition, it is inhibited by its end-product ascopyrone M [2] and it cannot convert ascopyrone M into microthecin, as can EC 4.2.1.110.
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, UM-BBD
References:
1.  Yu, S., Refdahl, C. and Lundt, I. Enzymatic description of the anhydrofructose pathway of glycogen degradation; I. Identification and purification of anhydrofructose dehydratase, ascopyrone tautomerase and α-1,4-glucan lyase in the fungus Anthracobia melaloma. Biochim. Biophys. Acta 1672 (2004) 120–129. [PMID: 15110094]
2.  Yu, S. and Fiskesund, R. The anhydrofructose pathway and its possible role in stress response and signaling. Biochim. Biophys. Acta 1760 (2006) 1314–1322. [PMID: 16822618]
3.  Yu, S. Enzymatic description of the anhydrofructose pathway of glycogen degradation. II. Gene identification and characterization of the reactions catalyzed by aldos-2-ulose dehydratase that converts 1,5-anhydro-D-fructose to microthecin with ascopyrone M as the intermediate. Biochim. Biophys. Acta 1723 (2005) 63–73. [PMID: 15716041]
[EC 4.2.1.111 created 2006]
 
 
EC 5.3.3.15
Transferred entry: ascopyrone tautomerase. Now EC 5.3.2.7, ascopyrone tautomerase
[EC 5.3.3.15 created 2006, deleted 2013]
 
 
EC 6.3.1.12
Accepted name: D-aspartate ligase
Reaction: ATP + D-aspartate + [β-GlcNAc-(1→4)-Mur2Ac(oyl-L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala)]n = [β-GlcNAc-(1→4)-Mur2Ac(oyl-L-Ala-γ-D-Glu-6-N-(β-D-Asp)-L-Lys-D-Ala-D-Ala)]n + ADP + phosphate
For diagram of reaction, click here
Other name(s): Aslfm; UDP-MurNAc-pentapeptide:D-aspartate ligase; D-aspartic acid-activating enzyme
Systematic name: D-aspartate:[β-GlcNAc-(1→4)-Mur2Ac(oyl-L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala)]n ligase (ADP-forming)
Comments: This enzyme forms part of the peptidoglycan assembly pathway of Gram-positive bacteria grown in medium containing D-Asp. Normally, the side chains the acylate the 6-amino group of the L-lysine residue contain L-Ala-L-Ala but these amino acids are replaced by D-Asp when D-Asp is included in the medium. Hybrid chains containing L-Ala-D-Asp, L-Ala-L-Ala-D-Asp or D-Asp-L-Ala are not formed [4]. The enzyme belongs in the ATP-grasp protein superfamily [3,4]. The enzyme is highly specific for D-aspartate, as L-aspartate, D-glutamate, D-alanine, D-iso-asparagine and D-malic acid are not substrates [4]. In Enterococcus faecium, the substrate D-aspartate is produced by EC 5.1.1.13, aspartate racemase [4]
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG
References:
1.  Staudenbauer, W. and Strominger, J.L. Activation of D-aspartic acid for incorporation into peptidoglycan. J. Biol. Chem. 247 (1972) 5095–5102. [PMID: 4262567]
2.  Staudenbauer, W., Willoughby, E. and Strominger, J.L. Further studies of the D-aspartic acid-activating enzyme of Streptococcus faecalis and its attachment to the membrane. J. Biol. Chem. 247 (1972) 5289–5296. [PMID: 4626717]
3.  Galperin, M.Y. and Koonin, E.V. A diverse superfamily of enzymes with ATP-dependent carboxylate-amine/thiol ligase activity. Protein Sci. 6 (1997) 2639–2643. [PMID: 9416615]
4.  Bellais, S., Arthur, M., Dubost, L., Hugonnet, J.E., Gutmann, L., van Heijenoort, J., Legrand, R., Brouard, J.P., Rice, L. and Mainardi, J.L. Aslfm, the D-aspartate ligase responsible for the addition of D-aspartic acid onto the peptidoglycan precursor of Enterococcus faecium. J. Biol. Chem. 281 (2006) 11586–11594. [PMID: 16510449]
[EC 6.3.1.12 created 2006]
 
 
EC 6.4.1.7
Accepted name: 2-oxoglutarate carboxylase
Reaction: ATP + 2-oxoglutarate + HCO3- = ADP + phosphate + oxalosuccinate
For diagram of reaction, click here
Glossary: oxalosuccinate = 1-oxopropane-1,2,3-tricarboxylate
Other name(s): oxalosuccinate synthetase; carboxylating factor for ICDH (incorrect); CFI; OGC
Comments: A biotin-containing enzyme that requires Mg2+ for activity. It was originally thought [1] that this enzyme was a promoting factor for the carboxylation of 2-oxoglutarate by EC 1.1.1.41, isocitrate dehydrogenase (NAD+), but this has since been disproved [2]. The product of the reaction is unstable and is quickly converted into isocitrate by the action of EC 1.1.1.41 [2].
Links to other databases: BRENDA, EXPASY, IUBMB, KEGG, CAS registry number: 60382-75-4
References:
1.  Aoshima, M., Ishii, M. and Igarashi, Y. A novel biotin protein required for reductive carboxylation of 2-oxoglutarate by isocitrate dehydrogenase in Hydrogenobacter thermophilus TK-6. Mol. Microbiol. 51 (2004) 791–798. [PMID: 14731279]
2.  Aoshima, M. and Igarashi, Y. A novel oxalosuccinate-forming enzyme involved in the reductive carboxylation of 2-oxoglutarate in Hydrogenobacter thermophilus TK-6. Mol. Microbiol. 62 (2006) 748–759. [PMID: 17076668]
[EC 6.4.1.7 created 2006]
 
 


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