IUBMB Enzyme Nomenclature

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

For diagram of reaction 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, ExplorEnz, KEGG, MetaCyc, 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. [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]

[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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