Vitamin K epoxide

Woodward-Eschenmoser method, 4, 431-440 neo-Vitamin B,2, 4, 421 Vitamin C — see Ascorbic acid Vitamin E — see a-Tocopherol Vitamin K epoxide, 7, 119 synthesis, 1, 439 Vitamins heterocyclic... 

In contrast to the formation and calcification of bones, vitamin K seems to lower the risk of aortic calcification. The mechanisms for these antagonistic effects is not known but a participation of osteocalcin (expressed in artherosclerotic plaques) as well as of matrix Gla protein (MGP) are discussed. In addition, the vitamin K epoxide reductase complex seems to be involved [5]. 

Spronk HM (2006) Vitamin K epoxide reductase complex and vascular calcification is this the important link between vitamin K and the arterial vessel wall Circulation 113 1550-1552... 

Goodstadt, L. and Ponting, C.P. (2004). Vitamin K epoxide reductase homology, active site and catalytic mechanism. Trends in Biochemical Science 29, 289-292. 

Robertson, H.M. (2004). Genes encoding vitamin K epoxide reductase are present in Drosophila and trypanosomatid protists. Genetics 168,1077-1080. 

Vitamin K is the cofactor for the carboxylation of glutamate residues in the post-synthetic modification of proteins to form the unusual amino acid y-carboxygluta-mate (Gla), which chelates the calcium ion. Initially, vitamin K hydroquinone is oxidized to the epoxide (Figure 45-8), which activates a glutamate residue in the protein substrate to a carbanion, that reacts non-enzymically with carbon dioxide to form y-carboxyglut-amate. Vitamin K epoxide is reduced to the quinone by a warfarin-sensitive reductase, and the quinone is reduced to the active hydroquinone by either the same warfarin-sensitive reductase or a warfarin-insensitive... 

Oral anticoagulants. Structurally related to vitamin K, 4-hydroxycouma-rins act as false vitamin K and prevent regeneration of reduced (active) vitamin I< from vitamin K epoxide, hence the synthesis of vitamin K-dependent clotting factors. 

Vitamin-K-epoxide reductase (warfarin-insensitive) [EC 1.1.4.2] catalyzes the reaction of 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone with oxidized dithiothreitol and water to produce 2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-l,4-naphthoquinone and 1,4-dithiothreitol. In the reverse reaction, vitamin K 2,3-epoxide is reduced to 3-hydroxy- (and 2-hydroxy-) vitamin K by 1,4-dithioerythritol (which is oxidized to the disulfide). The enzyme is not inhibited by warfarin. 

Mechanism of action Potentiates anti-protease activity of antithrombin III Inhibits vitamin K epoxide reductase... 

The proposal was supported by model experiments and also by observation of some incorporation of both atoms of 1802 into vitamin K epoxide. However, theoretical calculations support the simpler mechanism of Eq. 15-56. 

This synthetic compound, as well as natural coumarin anticoagulants (Box 15-F), inhibits both the vitamin K reductase and the epoxide reductase.518 519 The matter is of considerable practical importance because of the spread of warfarin-resistant rats in Europe and the United States. One resistance mutation has altered the vitamin K epoxide reductase so that it is much less susceptible to inhibition by warfarin.519 520... 

Vitamin K-dependent carboxylase uses vitamin K epoxidation to drive the carboxylation of glutamate groups in Gla domains. It is thought that reaction of oxygen with reduced vitamin K produces a strongly basic form of an... 

FIGURE 25-2 Role of vitamin K in the synthesis of vitamin K-dependent clotting factors (II, VII, IX and X). Vitamin K catalyzes the reaction necessary for completion of clotting factor synthesis, but it is oxidized in the process to vitamin K epoxide. Regeneration of vitamin K occurs via vitamin K epoxide reductase. Oral anticoagulants such as warfarin (Coumadin) block the regeneration of the vitamin K, thus halting the further synthesis of the vitamin K-dependent factors. 

Vitamin K cycle—metabolic interconversions of vitamin K associated with the synthesis of vitamin K-dependent clotting factors. Vitamin K1 or K2 is activated by reduction to the hydroquinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to prothrombin carboxylation by the enzyme carboxylase. The reactivation of vitamin K epoxide is the warfarin-sensitive step (warfarin). The R on the vitamin K molecule represents a 20-carbon phytyl side chain in vitamin Ki and a 30- to 65-carbon polyprenyl side chain in vitamin K2. 

Improved prediction of maintenance warfarin dose is linked to SNPs in the vitamin K epoxide reductase complex subunit... 

Aquilante, C.L. et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 2006, 79 291-302. 

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