Vitamin K-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... 

Vitamin K reductase epoxide complex International normalized ratio Thiopurine methyltransferase... 

FIGURE 4.2 The vitamin K cycle as it functions in protein glutamyl carboxylation reaction. The conversion of protein-bound glutamic acid into Y-carboxyglutamic acid is catalysed by a carboxylase. During the carboxylation reaction vitamin K hydroquinone (KH2) is converted to vitamin K epoxide (KO). X—(SH)2 and X—S2 represent, respectively, the reduced and oxidised forms of thioredoxin. The NADH-dependent and dithiol-dependent vitamin K reductases are different enzymes. Both the dithiol-dependent K- and KO-reductases are inhibited by dicoumarol (1) and warfarin (11). 

AD MacNicoll, AK Nadian, MG Townsend. Inhibition by warfarin of fiver microsomal vitamin K-reductase in warfarin-resistant and susceptible rats. Biochem Pharmacol 33(8) 1331—1336, 1984. 

Approximately 10% of patients require <1.5 mg/day of warfarin to achieve an INR of 2—3. These patients are more likely to possess one or two polymorphic alleles of CYP2C9, the major enzyme responsible for converting the S-enantiomer warfarin to its inactive metabolites. In comparison with the wild-type CYP2C9 1 allele, the variant alleles CYP2C9 2 and CYP2C9 3 have been shown to inactivate S-warfarin much less efficiently in vitro. The variant alleles are present in 10-20% of Caucasians, but in <5% of African Americans or Asians. Polymorphic variations in VKORCl, which encodes a component of the Vitamin K reductase complex (see Figure 54-6), also determine warfarin sensitivity. 

Fig. 45.5. A. Structures of vitamin K derivatives. Phylloquinone is found in green leaves, and intestinal bacteria synthesize menaquinone. Humans will convert menadione to a vitamin K active form. B. Vitamin K-dependent formation of y-carboxyglutamate residues. Thrombin, Factor VII, Factor IX, and Factor X are bound to their phospholipid activation sites on cell membranes by Ca ". The vitamin K-dependent carboxylase, which adds the extra carboxyl group, uses a reduced form of vitamin K (KH2) as the electron donor and converts vitamin K to an epxjx-ide. Vitamin K epoxide is reduced, in two steps, back to its active form by the enzymes vitamin K epoxide reductase and vitamin K reductase.

The classic vitamin K antagonist is warfarin. Warfarin acts by blocking the vitamin K reductase enzymes required to regenerate active vitamin K (see Fig. 45.5). This results in reduced y-carboxylation of Factors II, VII, IX, and X. In the absence of y-carboxylation, the factors cannot bind calcium nor form the complexes necessary for the coagulation cascade to be initiated. However, warfarin also blocks the activity of proteins S and C, so both blood clotting and the regulation of clotting are impaired by warfarin administration. 

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... 

Mammalian thioredoxin reductase is able to reduce many substances in addition to thioredoxin such as insulin, vitamin K, alloxan, and others, while Escherichia coli enzyme is a... 

T. M. Guenthner, D. Cai, R. Wallin, Co-Purification of Microsomal Epoxide Hydrolase with the Warfarin-Sensitive Vitamin Kx Oxide Reductase of the Vitamin K Cycle , Biochem. Pharmacol. 1998, 55, 169 - 175. 

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... 

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