EC |
1.14.99.20 |
Accepted name: |
phylloquinone monooxygenase (2,3-epoxidizing) |
Reaction: |
phylloquinone + reduced acceptor + O2 = 2,3-epoxyphylloquinone + acceptor + H2O |
Other name(s): |
phylloquinone epoxidase; vitamin K 2,3-epoxidase; vitamin K epoxidase; vitamin K1 epoxidase |
Systematic name: |
phylloquinone,hydrogen-donor:oxygen oxidoreductase (2,3-epoxidizing) |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 54596-37-1 |
References: |
1. |
Willingham, A.K. and Matschiner, J.T. Changes in phylloquinone epoxidase activity related to prothrombin synthesis and microsomal clotting activity in the rat. Biochem. J. 140 (1974) 435–441. [PMID: 4155625] |
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[EC 1.14.99.20 created 1976] |
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EC |
1.17.4.4 |
Accepted name: |
vitamin-K-epoxide reductase (warfarin-sensitive) |
Reaction: |
(1) phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues (2) phylloquinol + a protein with a disulfide bond = phylloquinone + a protein with reduced L-cysteine residues |
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For diagram of the vitamin K cycle, click here |
Glossary: |
phylloquinone = vitamin K1 = 2-methyl-3-phytyl-1,4-naphthoquinone
2,3-epoxyphylloquinone = vitamin K1 2,3-epoxide = 2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone |
Other name(s): |
VKORC1 (gene name); VKORC1L1 (gene name) |
Systematic name: |
phylloquinone:disulfide oxidoreductase |
Comments: |
The enzyme catalyses the reduction of vitamin K 2,3-epoxide, which is formed by the activity of EC 4.1.1.90, peptidyl-glutamate 4-carboxylase, back to its phylloquinol active form. The enzyme forms a tight complex with EC 5.3.4.1, protein disulfide-isomerase, which transfers the required electrons from newly-synthesized proteins by catalysing the formation of disulfide bridges. The enzyme acts on the epoxide forms of both phylloquinone (vitamin K1) and menaquinone (vitamin K2). Inhibited strongly by (S)-warfarin and ferulenol. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 55963-40-1 |
References: |
1. |
Whitlon, D.S., Sadowski, J.A. and Suttie, J.W. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 17 (1978) 1371–1377. [PMID: 646989] |
2. |
Lee, J.L. and Fasco, M.J. Metabolism of vitamin K and vitamin K 2,3-epoxide via interaction with a common disulfide. Biochemistry 23 (1984) 2246–2252. [PMID: 6733086] |
3. |
Mukharji, I. and Silverman, R.B. Purification of a vitamin K epoxide reductase that catalyzes conversion of vitamin K 2,3-epoxide to 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone. Proc. Natl. Acad. Sci. USA 82 (1985) 2713–2717. [DOI] [PMID: 3857611] |
4. |
Li, T., Chang, C.Y., Jin, D.Y., Lin, P.J., Khvorova, A. and Stafford, D.W. Identification of the gene for vitamin K epoxide reductase. Nature 427 (2004) 541–544. [PMID: 14765195] |
5. |
Wajih, N., Hutson, S.M. and Wallin, R. Disulfide-dependent protein folding is linked to operation of the vitamin K cycle in the endoplasmic reticulum. A protein disulfide isomerase-VKORC1 redox enzyme complex appears to be responsible for vitamin K1 2,3-epoxide reduction. J. Biol. Chem. 282 (2007) 2626–2635. [PMID: 17124179] |
6. |
Spohn, G., Kleinridders, A., Wunderlich, F.T., Watzka, M., Zaucke, F., Blumbach, K., Geisen, C., Seifried, E., Muller, C., Paulsson, M., Bruning, J.C. and Oldenburg, J. VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding. Thromb Haemost 101 (2009) 1044–1050. [PMID: 19492146] |
7. |
Schulman, S., Wang, B., Li, W. and Rapoport, T.A. Vitamin K epoxide reductase prefers ER membrane-anchored thioredoxin-like redox partners. Proc. Natl. Acad. Sci. USA 107 (2010) 15027–15032. [PMID: 20696932] |
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[EC 1.17.4.4 created 1989 as EC 1.1.4.1, transferred 2014 to EC 1.17.4.4, modified 2018] |
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EC |
4.1.1.90 |
Accepted name: |
peptidyl-glutamate 4-carboxylase |
Reaction: |
peptidyl-4-carboxyglutamate + 2,3-epoxyphylloquinone + H2O = peptidyl-glutamate + CO2 + O2 + phylloquinol |
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For diagram of the vitamin K cycle, click here |
Other name(s): |
vitamin K-dependent carboxylase; γ-glutamyl carboxylase; peptidyl-glutamate 4-carboxylase (2-methyl-3-phytyl-1,4-naphthoquinone-epoxidizing) |
Systematic name: |
peptidyl-glutamate 4-carboxylase (2-methyl-3-phytyl-1,4-naphthoquinol-epoxidizing) |
Comments: |
The enzyme can use various vitamin-K derivatives, including menaquinol, but does not contain iron. The mechanism appears to involve the generation of a strong base by oxygenation of vitamin K. It catalyses the post-translational carboxylation of glutamate residues of several proteins of the blood-clotting system. 9–12 glutamate residues are converted to 4-carboxyglutamate (Gla) in a specific domain of the target protein. The 4-pro-S hydrogen of the glutamate residue is removed [5] and there is an inversion of stereochemistry at this position [6]. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc |
References: |
1. |
Dowd, P., Hershline, R., Ham, S.W. and Naganathan, S. Vitamin K and energy transduction: a base strength amplification mechanism. Science 269 (1995) 1684–1691. [DOI] [PMID: 7569894] |
2. |
Furie, B., Bouchard, B.A. and Furie, B.C. Vitamin K-dependent biosynthesis of γ-carboxyglutamic acid. Blood 93 (1999) 1798–1808. [PMID: 10068650] |
3. |
Rishavy, M.A., Hallgren, K.W., Yakubenko, A.V., Shtofman, R.L., Runge, K.W. and Berkner, K.L. Bronsted analysis reveals Lys218 as the carboxylase active site base that deprotonates vitamin K hydroquinone to initiate vitamin K-dependent protein carboxylation. Biochemistry 45 (2006) 13239–13248. [DOI] [PMID: 17073445] |
4. |
Silva, P.J. and Ramos, M.J. Reaction mechanism of the vitamin K-dependent glutamate carboxylase: a computational study. J. Phys. Chem. B 111 (2007) 12883–12887. [DOI] [PMID: 17935315] |
5. |
Decottignies-Le Maréchal, P., Ducrocq, C., Marquet, A. and Azerad, R. The stereochemistry of hydrogen abstraction in vitamin K-dependent carboxylation. J. Biol. Chem. 259 (1984) 15010–15012. [PMID: 6150930] |
6. |
Dubois, J., Dugave, C., Foures, C., Kaminsky, M., Tabet, J.C., Bory, S., Gaudry, M. and Marquet, A. Vitamin K dependent carboxylation: determination of the stereochemical course using 4-fluoroglutamyl-containing substrate. Biochemistry 30 (1991) 10506–10512. [PMID: 1931973] |
7. |
Rishavy, M.A. and Berkner, K.L. Vitamin K oxygenation, glutamate carboxylation, and processivity: defining the three critical facets of catalysis by the vitamin K-dependent carboxylase. Adv Nutr 3 (2012) 135–148. [DOI] [PMID: 22516721] |
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[EC 4.1.1.90 created 2009, modified 2011] |
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