Vitamin K-2,3-epoxide reductase

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-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... 

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... 

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. 

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. 

Hildebrand EF, Preusch PC, Patterson JL, and Suttie JW (1984) Solubilization and characterization of vitamin K epoxide reductase from normal and warfarin-resistant rat liver microsomes. Archives of Biochemistry and Biophysics 228,480-92. 

Dicumarol competitively inhibits vitamin K epoxide reductase. 

Extraction of the proton allows the carboxylase to carbox-ylate the glutamate residue. The vitamin K intermediate is converted to vitamin K oxide, which must be reduced back to vitamin K. Vitamin K oxide is recycled back to vitamin K by vitamin K epoxide reductase arid vitamin K quinone reducta.se. Both of these enzymes are dithiol dependent and are inhibited by the 4-hydroxycoumarin anticoagulants. 

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