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] |
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[EC 1.1.1.104 created 1972, modified 2022] |
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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] |
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[EC 1.5.5.3 created 2017] |
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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 |
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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] |
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[EC 1.14.11.2 created 1972, modified 1981, modified 1983, modified 2017] |
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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] |
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[EC 1.14.11.28 created 2006] |
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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] |
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[EC 1.14.11.29 created 2010] |
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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] |
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[EC 1.14.11.57 created 2017] |
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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] |
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[EC 2.4.1.229 created 2003, modified 2013] |
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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] |
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[EC 2.4.2.58 created 2016] |
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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 |
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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] |
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[EC 2.6.1.23 created 1972, modified 1982, modified 2020] |
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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] |
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[EC 4.2.1.172 created 2017] |
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EC |
5.1.1.8 |
Accepted name: |
4-hydroxyproline epimerase |
Reaction: |
trans-4-hydroxy-L-proline = cis-4-hydroxy-D-proline |
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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] |
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[EC 5.1.1.8 created 1965, modified 1983] |
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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] |
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[EC 5.1.1.22 created 2017] |
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