EC 1.6.5.12     
Accepted name: demethylphylloquinone reductase
Reaction: demethylphylloquinone + NADPH + H+ = demethylphylloquinol + NADP+
Glossary: demethylphylloquinone = 2-phytyl-1,4-naphthoquinone
Other name(s): ndbB (gene name); NDC1 (gene name); demethylphylloquinone:NADPH oxidoreductase
Systematic name: NADPH:demethylphylloquinone oxidoreductase
Comments: The enzyme, found in plants and cyanobacteria, is involved in the biosynthesis of phylloquinone (vitamin K1), an electron carrier associated with photosystem I. The enzyme is a type II NADPH dehydrogenase and requires a flavine adenine dinucleotide cofactor.
References:
1.  Fatihi, A., Latimer, S., Schmollinger, S., Block, A., Dussault, P.H., Vermaas, W.F., Merchant, S.S. and Basset, G.J. A dedicated type II NADPH dehydrogenase performs the penultimate step in the biosynthesis of vitamin K1 in Synechocystis and Arabidopsis. Plant Cell 27 (2015) 1730–1741. [PMID: 26023160]
[EC 1.6.5.12 created 2015]
 
 
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
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.
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]
 
 
EC 2.1.1.329     
Accepted name: demethylphylloquinol methyltransferase
Reaction: S-adenosyl-L-methionine + demethylphylloquinol = S-adenosyl-L-homocysteine + phylloquinol
Glossary: demethylphylloquinol = 2-phytyl-1,4-naphthoquinol
phylloquinol = 2-methyl-3-phytyl-1,4-naphthoquinol = vitamin K1
Other name(s): menG (gene name); 2-phytyl-1,4-naphthoquinol methyltransferase
Systematic name: S-adenosyl-L-methionine:2-phytyl-1,4-naphthoquinol C-methyltransferase
Comments: The enzyme, found in plants and cyanobacteria, catalyses the final step in the biosynthesis of phylloquinone (vitamin K1), an electron carrier associated with photosystem I. The enzyme is specific for the quinol form of the substrate, and does not act on the quinone form [3].
References:
1.  Sakuragi, Y., Zybailov, B., Shen, G., Jones, A.D., Chitnis, P.R., van der Est, A., Bittl, R., Zech, S., Stehlik, D., Golbeck, J.H. and Bryant, D.A. Insertional inactivation of the menG gene, encoding 2-phytyl-1,4-naphthoquinone methyltransferase of Synechocystis sp. PCC 6803, results in the incorporation of 2-phytyl-1,4-naphthoquinone into the A1 site and alteration of the equilibrium constant between A1 and F(X) in photosystem I. Biochemistry 41 (2002) 394–405. [PMID: 11772039]
2.  Lohmann, A., Schottler, M.A., Brehelin, C., Kessler, F., Bock, R., Cahoon, E.B. and Dormann, P. Deficiency in phylloquinone (vitamin K1) methylation affects prenyl quinone distribution, photosystem I abundance, and anthocyanin accumulation in the Arabidopsis AtmenG mutant. J. Biol. Chem. 281 (2006) 40461–40472. [PMID: 17082184]
3.  Fatihi, A., Latimer, S., Schmollinger, S., Block, A., Dussault, P.H., Vermaas, W.F., Merchant, S.S. and Basset, G.J. A dedicated type II NADPH dehydrogenase performs the penultimate step in the biosynthesis of vitamin K1 in Synechocystis and Arabidopsis. Plant Cell 27 (2015) 1730–1741. [PMID: 26023160]
[EC 2.1.1.329 created 2016]
 
 
EC 4.1.1.90     
Accepted name: peptidyl-glutamate 4-carboxylase
Reaction: peptidyl-4-carboxyglutamate + 2,3-epoxyphylloquinone + H2O = peptidyl-glutamate + CO2 + O2 + phylloquinol
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].
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. [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. [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. [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. [PMID: 22516721]
[EC 4.1.1.90 created 2009, modified 2011]