The Enzyme Database

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EC 1.1.1.104     
Accepted name: 4-oxoproline reductase
Reaction: cis-4-hydroxy-L-proline + NAD+ = 4-oxo-L-proline + NADH + H+
Other name(s): cis-hydroxy-L-proline oxidase
Systematic name: cis-4-hydroxy-L-proline:NAD+ oxidoreductase (4-oxo-L-proline forming)
Comments: The enzyme, isolated from animals, is specific for 4-oxo-L-proline and cis-4-hydroxy-L-proline. It has no activity with trans-4-hydroxy-L-proline.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 37250-37-6
References:
1.  Smith, T.E. and Mitoma, C. Partial purification and some properties of 4-ketoproline reductase. J. Biol. Chem. 237 (1962) 1177–1180. [PMID: 13914427]
2.  Kwiatkowski, S., Bozko, M., Zarod, M., Witecka, A., Kocdemir, K., Jagielski, A.K. and Drozak, J. Recharacterization of the mammalian cytosolic type 2 (R)-β-hydroxybutyrate dehydrogenase (BDH2) as 4-oxo-L-proline reductase (EC 1.1.1.104). J. Biol. Chem. 298:101708 (2022). [DOI] [PMID: 35150746]
[EC 1.1.1.104 created 1972, modified 2022]
 
 
EC 1.5.5.3     
Accepted name: hydroxyproline dehydrogenase
Reaction: trans-4-hydroxy-L-proline + a quinone = (3R,5S)-3-hydroxy-1-pyrroline-5-carboxylate + a quinol
Other name(s): HYPDH; OH-POX; hydroxyproline oxidase; PRODH2 (gene name)
Systematic name: trans-4-hydroxy-L-proline:quinone oxidoreductase
Comments: A flavoprotein (FAD). The enzyme from human also has low activity with L-proline (cf. EC 1.5.5.2, proline dehydrogenase).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Cooper, S.K., Pandhare, J., Donald, S.P. and Phang, J.M. A novel function for hydroxyproline oxidase in apoptosis through generation of reactive oxygen species. J. Biol. Chem. 283 (2008) 10485–10492. [DOI] [PMID: 18287100]
2.  Summitt, C.B., Johnson, L.C., Jonsson, T.J., Parsonage, D., Holmes, R.P. and Lowther, W.T. Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. Biochem. J. 466 (2015) 273–281. [DOI] [PMID: 25697095]
[EC 1.5.5.3 created 2017]
 
 
EC 1.14.11.2     
Accepted name: procollagen-proline 4-dioxygenase
Reaction: procollagen L-proline + 2-oxoglutarate + O2 = procollagen trans-4-hydroxy-L-proline + succinate + CO2
For diagram of reaction, click here
Other name(s): P4HA (gene name); P4HB (gene name); protocollagen hydroxylase; proline hydroxylase; proline,2-oxoglutarate 4-dioxygenase; collagen proline hydroxylase; hydroxylase, collagen proline; peptidyl proline hydroxylase; proline protocollagen hydroxylase; proline, 2-oxoglutarate dioxygenase; prolyl hydroxylase; prolylprotocollagen dioxygenase; prolylprotocollagen hydroxylase; protocollagen proline 4-hydroxylase; protocollagen proline dioxygenase; protocollagen proline hydroxylase; protocollagen prolyl hydroxylase; prolyl 4-hydroxylase; prolyl-glycyl-peptide, 2-oxoglutarate:oxygen oxidoreductase, 4-hydroxylating; procollagen-proline 4-dioxygenase (ambiguous)
Systematic name: procollagen-L-proline,2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Comments: Requires Fe2+ and ascorbate.The enzyme, which is located within the lumen of the endoplasmic reticulum, catalyses the 4-hydroxylation of prolines in -X-Pro-Gly- sequences. The 4-hydroxyproline residues are essential for the formation of the collagen triple helix. The enzyme forms a complex with protein disulfide isomerase and acts not only on procollagen but also on more than 15 other proteins that have collagen-like domains.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9028-06-2
References:
1.  Hutton, J.J., Jr., Tappel, A.L. and Udenfriend, S. Cofactor and substrate requirements of collagen proline hydroxylase. Arch. Biochem. Biophys. 118 (1967) 231–240.
2.  Kivirikko, K.I. and Prockop, D.J. Purification and partial characterization of the enzyme for the hydroxylation of proline in protocollogen. Arch. Biochem. Biophys. 118 (1967) 611–618.
3.  Kivirikko, K.I., Kishida, Y., Sakakibara, S. and Prockop, J. Hydroxylation of (X-Pro-Gly)n by protocollagen proline hydroxylase. Effect of chain length, helical conformation and amino acid sequence in the substrate. Biochim. Biophys. Acta 271 (1972) 347–356. [DOI] [PMID: 5046811]
4.  Berg, R.A. and Prockop, D.J. Affinity column purification of protocollagen proline hydroxylase from chick embryos and further characterization of the enzyme. J. Biol. Chem. 248 (1973) 1175–1182. [PMID: 4346946]
5.  John, D.C. and Bulleid, N.J. Prolyl 4-hydroxylase: defective assembly of α-subunit mutants indicates that assembled α-subunits are intramolecularly disulfide bonded. Biochemistry 33 (1994) 14018–14025. [PMID: 7947811]
6.  Lamberg, A., Pihlajaniemi, T. and Kivirikko, K.I. Site-directed mutagenesis of the α subunit of human prolyl 4-hydroxylase. Identification of three histidine residues critical for catalytic activity. J. Biol. Chem. 270 (1995) 9926–9931. [DOI] [PMID: 7730375]
7.  Myllyharju, J. and Kivirikko, K.I. Characterization of the iron- and 2-oxoglutarate-binding sites of human prolyl 4-hydroxylase. EMBO J. 16 (1997) 1173–1180. [DOI] [PMID: 9135134]
8.  Kivirikko, K.I. and Myllyharju, J. Prolyl 4-hydroxylases and their protein disulfide isomerase subunit. Matrix Biol 16 (1998) 357–368. [DOI] [PMID: 9524356]
[EC 1.14.11.2 created 1972, modified 1981, modified 1983, modified 2017]
 
 
EC 1.14.11.28     
Accepted name: proline 3-hydroxylase
Reaction: L-proline + 2-oxoglutarate + O2 = cis-3-hydroxy-L-proline + succinate + CO2
For diagram of reaction, click here
Other name(s): P-3-H
Systematic name: L-proline,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating)
Comments: Requires iron(II) for activity. Unlike the proline hydroxylases involved in collagen biosynthesis [EC 1.14.11.2 (procollagen-proline dioxygenase) and EC 1.14.11.7 (procollagen-proline 3-dioxygenase)], this enzyme does not require ascorbate for activity although it does increase the activity of the enzyme [2]. The enzyme is specific for L-proline as D-proline, trans-4-hydroxy-L-proline, cis-4-hydroxy-L-proline and 3,4-dehydro-DL-proline are not substrates [2].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 162995-24-6
References:
1.  Mori, H., Shibasaki, T., Uozaki, Y., Ochiai, K. and Ozaki, A. Detection of novel proline 3-hydroxylase activities in Streptomyces and Bacillus spp. by regio- and stereospecific hydroxylation of L-proline. Appl. Environ. Microbiol. 62 (1996) 1903–1907. [PMID: 16535329]
2.  Mori, H., Shibasaki, T., Yano, K. and Ozaki, A. Purification and cloning of a proline 3-hydroxylase, a novel enzyme which hydroxylates free L-proline to cis-3-hydroxy-L-proline. J. Bacteriol. 179 (1997) 5677–5683. [DOI] [PMID: 9294421]
3.  Clifton, I.J., Hsueh, L.C., Baldwin, J.E., Harlos, K. and Schofield, C.J. Structure of proline 3-hydroxylase. Evolution of the family of 2-oxoglutarate dependent oxygenases. Eur. J. Biochem. 268 (2001) 6625–6636. [DOI] [PMID: 11737217]
[EC 1.14.11.28 created 2006]
 
 
EC 1.14.11.29     
Accepted name: hypoxia-inducible factor-proline dioxygenase
Reaction: hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2 = hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
Other name(s): HIF hydroxylase
Systematic name: hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Comments: Contains iron, and requires ascorbate. Specifically hydroxylates a proline residue in HIF-α, the α subunit of the transcriptional regulator HIF (hypoxia-inducible factor), which targets HIF for proteasomal destruction. The requirement of oxygen for the hydroxylation reaction enables animals to respond to hypoxia.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Jaakkola, P., Mole, D.R., Tian, Y.M., Wilson, M.I., Gielbert, J., Gaskell, S.J., Kriegsheim Av, Hebestreit, H.F., Mukherji, M., Schofield, C.J., Maxwell, P.H., Pugh, C.W. and Ratcliffe, P.J. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292 (2001) 468–472. [DOI] [PMID: 11292861]
2.  Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J.M., Lane, W.S. and Kaelin , W.G., Jr. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292 (2001) 464–468. [DOI] [PMID: 11292862]
3.  Bruick, R.K. and McKnight, S.L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294 (2001) 1337–1340. [DOI] [PMID: 11598268]
4.  Epstein, A.C., Gleadle, J.M., McNeill, L.A., Hewitson, K.S., O'Rourke, J., Mole, D.R., Mukherji, M., Metzen, E., Wilson, M.I., Dhanda, A., Tian, Y.M., Masson, N., Hamilton, D.L., Jaakkola, P., Barstead, R., Hodgkin, J., Maxwell, P.H., Pugh, C.W., Schofield, C.J. and Ratcliffe, P.J. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107 (2001) 43–54. [DOI] [PMID: 11595184]
5.  Oehme, F., Ellinghaus, P., Kolkhof, P., Smith, T.J., Ramakrishnan, S., Hutter, J., Schramm, M. and Flamme, I. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem. Biophys. Res. Commun. 296 (2002) 343–349. [DOI] [PMID: 12163023]
6.  McNeill, L.A., Hewitson, K.S., Gleadle, J.M., Horsfall, L.E., Oldham, N.J., Maxwell, P.H., Pugh, C.W., Ratcliffe, P.J. and Schofield, C.J. The use of dioxygen by HIF prolyl hydroxylase (PHD1). Bioorg. Med. Chem. Lett. 12 (2002) 1547–1550. [DOI] [PMID: 12039559]
[EC 1.14.11.29 created 2010]
 
 
EC 1.14.11.57     
Accepted name: L-proline trans-4-hydroxylase
Reaction: L-proline + 2-oxoglutarate + O2 = trans-4-hydroxy-L-proline + succinate + CO2
Systematic name: L-proline,2-oxoglutarate:oxygen oxidoreductase (trans-4-hydroxylating)
Comments: Requires Fe2+ and ascorbate. The enzyme, isolated from multiple bacterial species, only produces trans-4-hydroxy-L-proline (cf. EC 1.14.11.56, L-proline cis-4-hydroxylase).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Lawrence, C.C., Sobey, W.J., Field, R.A., Baldwin, J.E. and Schofield, C.J. Purification and initial characterization of proline 4-hydroxylase from Streptomyces griseoviridus P8648: a 2-oxoacid, ferrous-dependent dioxygenase involved in etamycin biosynthesis. Biochem. J. 313 (1996) 185–191. [PMID: 8546682]
2.  Shibasaki, T., Mori, H., Chiba, S. and Ozaki, A. Microbial proline 4-hydroxylase screening and gene cloning. Appl. Environ. Microbiol. 65 (1999) 4028–4031. [PMID: 10473412]
[EC 1.14.11.57 created 2017]
 
 
EC 2.4.1.229     
Accepted name: [Skp1-protein]-hydroxyproline N-acetylglucosaminyltransferase
Reaction: UDP-N-acetyl-α-D-glucosamine + [Skp1-protein]-trans-4-hydroxy-L-proline = UDP + [Skp1-protein]-O-(N-acetyl-α-D-glucosaminyl)-trans-4-hydroxy-L-proline
Other name(s): Skp1-HyPro GlcNAc-transferase; UDP-N-acetylglucosamine (GlcNAc):hydroxyproline polypeptide GlcNAc-transferase; UDP-GlcNAc:Skp1-hydroxyproline GlcNAc-transferase; UDP-GlcNAc:hydroxyproline polypeptide GlcNAc-transferase; UDP-N-acetyl-D-glucosamine:[Skp1-protein]-hydroxyproline N-acetyl-D-glucosaminyl-transferase
Systematic name: UDP-N-acetyl-α-D-glucosamine:[Skp1-protein]-trans-4-hydroxy-L-proline N-acetyl-α-D-glucosaminyl-transferase
Comments: Skp1 is a cytoplasmic and nuclear protein required for the ubiquitination of cell cycle regulatory proteins and transcriptional factors. In Dictyostelium Skp1 is modified by the linear pentasaccharide Galα1-6Galα1-L-Fucα1-2Galβ1-3GlcNAc, which is attached to a hydroxyproline residue at position 143. This enzyme catalyses the first step in the building up of the pentasaccharide by attaching an N-acetylglucosaminyl group to the hydroxyproline residue. It requires dithiothreitol and a divalent cation for activity.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 256531-81-4
References:
1.  van der Wel, H., Morris, H.R., Panico, M., Paxton, T., Dell, A., Kaplan, L. and West, C.M. Molecular cloning and expression of a UDP-N-acetylglucosamine (GlcNAc):hydroxyproline polypeptide GlcNAc-transferase that modifies Skp1 in the cytoplasm of Dictyostelium. J. Biol. Chem. 277 (2002) 46328–46337. [DOI] [PMID: 12244115]
2.  Teng-umnuay, P., van der Wel, H. and West, C.M. Identification of a UDP-GlcNAc:Skp1-hydroxyproline GlcNAc-transferase in the cytoplasm of Dictyostelium. J. Biol. Chem. 274 (1999) 36392–36402. [DOI] [PMID: 10593934]
3.  West, C.M., van der Wel, H. and Gaucher, E.A. Complex glycosylation of Skp1 in Dictyostelium: implications for the modification of other eukaryotic cytoplasmic and nuclear proteins. Glycobiology 12 (2002) 17. [DOI] [PMID: 11886837]
[EC 2.4.1.229 created 2003, modified 2013]
 
 
EC 2.4.2.58     
Accepted name: hydroxyproline O-arabinosyltransferase
Reaction: UDP-β-L-arabinofuranose + [protein]-trans-4-hydroxy-L-proline = UDP + [protein]-trans-4-(β-L-arabinofuranosyl)oxy-L-proline
Glossary: trans-4-hydroxy-L-proline = (2S,4R)-4-hydroxyproline = (4R)-4-hydroxy-L-proline
Other name(s): HPAT
Systematic name: UDP-β-L-arabinofuranose:[protein]-trans-4-hydroxy-L-proline L-arabinofuranosyl transferase (configuration-retaining)
Comments: The enzyme, found in plants and mosses, catalyses the O-arabinosylation of hydroxyprolines in hydroxyproline-rich glycoproteins. The enzyme acts on the first hydroxyproline in the motif Val-hydroxyPro-hydroxyPro-Ser.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Ogawa-Ohnishi, M., Matsushita, W. and Matsubayashi, Y. Identification of three hydroxyproline O-arabinosyltransferases in Arabidopsis thaliana. Nat. Chem. Biol. 9 (2013) 726–730. [DOI] [PMID: 24036508]
[EC 2.4.2.58 created 2016]
 
 
EC 2.6.1.23     
Accepted name: 4-hydroxyglutamate transaminase
Reaction: erythro-4-hydroxy-L-glutamate + 2-oxoglutarate = (4R)-4-hydroxy-2-oxoglutarate + L-glutamate
For diagram of reaction, click here and for mechanism, click here
Glossary: erythro-4-hydroxy-L-glutamate = (2S,4R)-2-amino-4-hydroxypentanedioate
Other name(s): 4-hydroxyglutamate aminotransferase; 4-hydroxy-L-glutamate:2-oxoglutarate aminotransferase
Systematic name: erythro-4-hydroxy-L-glutamate:2-oxoglutarate aminotransferase
Comments: The enzyme participates in a degradation pathway of trans-4-hydroxy-L-proline, a compound that contributes to the stability of the collagen triple helix. Oxaloacetate can replace 2-oxoglutarate. This enzyme may be identical with EC 2.6.1.1 aspartate transaminase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 37277-86-4
References:
1.  Goldstone, A. and Adams, E. Metabolism of γ-hydroxyglutamic acid. I. Conversion to α-hydroxy-γ-ketoglutarate by purified glutamic-aspartic transaminase to rat liver. J. Biol. Chem. 237 (1962) 3476–3485. [PMID: 13948827]
2.  Kuratomi, K., Fukunaga, K. and Kobayashi, Y. The metabolism of γ-hydroxyglutamate in rat liver. II. A transaminase concerned in γ-hydroxyglutamate metabolism. Biochim. Biophys. Acta 78 (1963) 629–636. [DOI] [PMID: 14089443]
3.  Maitra U, Deekker E Purification of rat-liver γ-hydroxyglutamate transaminase and its probable identity with glutamate-aspartate transaminase. Biochim. Biophys. Acta 81 (1964) 517–532. [PMID: 14170323]
[EC 2.6.1.23 created 1972, modified 1982, modified 2020]
 
 
EC 4.2.1.172     
Accepted name: trans-4-hydroxy-L-proline dehydratase
Reaction: trans-4-hydroxy-L-proline = (S)-1-pyrroline-5-carboxylate + H2O
Glossary: 1-pyrroline = 3,4-dihydro-2H-pyrrole
Systematic name: trans-4-hydroxy-L-proline hydro-lyase
Comments: The enzyme has been characterized from the bacterium Peptoclostridium difficile. The active form contains a glycyl radical that is generated by a dedicated activating enzyme via chemistry involving S-adenosyl-L-methionine (SAM) and a [4Fe-4S] cluster.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Levin, B.J., Huang, Y.Y., Peck, S.C., Wei, Y., Martinez-Del Campo, A., Marks, J.A., Franzosa, E.A., Huttenhower, C. and Balskus, E.P. A prominent glycyl radical enzyme in human gut microbiomes metabolizes trans-4-hydroxy-L-proline. Science 355 (2017) . [DOI] [PMID: 28183913]
[EC 4.2.1.172 created 2017]
 
 
EC 5.1.1.8     
Accepted name: 4-hydroxyproline epimerase
Reaction: trans-4-hydroxy-L-proline = cis-4-hydroxy-D-proline
For diagram of reaction, click here
Other name(s): hydroxyproline epimerase; hydroxyproline 2-epimerase; L-hydroxyproline epimerase
Systematic name: 4-hydroxyproline 2-epimerase
Comments: Also interconverts trans-4-hydroxy-D-proline and cis-4-hydroxy-L-proline.
Links to other databases: BRENDA, EXPASY, GTD, KEGG, MetaCyc, PDB, CAS registry number: 9024-23-1
References:
1.  Adams, E. and Norton, I.L. Purification and properties of inducible hydroxyproline 2-epimerase from Pseudomonas. J. Biol. Chem. 239 (1964) 1525–1535. [PMID: 14189888]
[EC 5.1.1.8 created 1965, modified 1983]
 
 
EC 5.1.1.22     
Accepted name: 4-hydroxyproline betaine 2-epimerase
Reaction: (1) trans-4-hydroxy-L-proline betaine = cis-4-hydroxy-D-proline betaine
(2) L-proline betaine = D-proline betaine
Glossary: trans-4-hydroxy-L-proline betaine = (2S,4R)-4-hydroxy-1,1-dimethylpyrrolidinium-2-carboxylate
cis-4-hydroxy-D-proline betaine = (2R,4R)-4-hydroxy-1,1-dimethylpyrrolidinium-2-carboxylate
L-proline betaine = (2S)-1,1-dimethylpyrrolidinium-2-carboxylate
D-proline betaine = (2R)-1,1-dimethylpyrrolidinium-2-carboxylate
Other name(s): hpbD (gene name); Hyp-B 2-epimerase; (4R)-4-hydroxyproline betaine 2-epimerase
Systematic name: 4-hydroxyproline betaine 2-epimerase
Comments: The enzyme, characterized from the bacteria Pelagibaca bermudensis and Paracoccus denitrificans, specifically catalyses racemization of trans-4-hydroxy-L-proline betaine and L-proline betaine at the C-2 position.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Zhao, S., Kumar, R., Sakai, A., Vetting, M.W., Wood, B.M., Brown, S., Bonanno, J.B., Hillerich, B.S., Seidel, R.D., Babbitt, P.C., Almo, S.C., Sweedler, J.V., Gerlt, J.A., Cronan, J.E. and Jacobson, M.P. Discovery of new enzymes and metabolic pathways by using structure and genome context. Nature 502 (2013) 698–702. [DOI] [PMID: 24056934]
2.  Kumar, R., Zhao, S., Vetting, M.W., Wood, B.M., Sakai, A., Cho, K., Solbiati, J., Almo, S.C., Sweedler, J.V., Jacobson, M.P., Gerlt, J.A. and Cronan, J.E. Prediction and biochemical demonstration of a catabolic pathway for the osmoprotectant proline betaine. MBio 5 (2014) e00933. [DOI] [PMID: 24520058]
[EC 5.1.1.22 created 2017]
 
 


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