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... 

Veenstra DL, Ydu JH, Rieder MJ, et al. Association of vit K epoxide reductase complex I (VKORKCI) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics 2005 15 687-691. 

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. 

Vitamin K quinone is reduced to the active hydroquinone substrate for the epoxidase reaction by either a dithiol-linked reductase that is almost certainly the same enzyme as the epoxide reductase or NADPH-dependent quinone reductase, like the epoxide reductase, the dithiol-linked reductase is inhibited by warfarin. In warfarin-resistant rats, there is a warfarin-insensitive epoxide reductase, which also has quinone reductase activity (Hildebrandt et al., 1984 Gardill and Suttie, 1990). 

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. 

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