Vitamin K quinone reductase

Very high intakes may antagonize vitamin K and hence potentiate anticoagulant therapy. This is probably the result of inhibition of the vitamin K quinone reductase, but a-tocopheryl quinone may compete with vitamin K hydroquinone and hence inhibit carboxylation of glutamate in target proteins (Section 5.3.1). 

All are probably bound to the microsomal membranes.503 507a An NADPH-dependent reductase reduces vitamin K quinone to its hydroquinone form. Conversion of Glu residues to Gla residues requires this reduced vitamin K as well as 02 and C02. During the carboxy-lation reaction the reduced vitamin K is converted into vitamin K 2,3-epoxide (Eq. 15-55).508 The mechanism is uncertain but a peroxide intermediate such as that shown in Eq. 15-56 is probably involved. This could be used to generate a hydroxide ion adjacent to the pro-S -H of the glutamate side chain of the substrate. This hydrogen could be abstracted by the OH to form... 

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). 

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. 

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... 

Figure 5.2. Reaction of the vitamin K-dependent carboxylase (vitamin K epoxidase) and recycling of vitamin K epoxide to the hydroquinone. Vitamin K epoxidase, EC 1.14.99.20 warfarin-sensitive epoxide/quinone reductase, EC 1.1.4.1 and warfarin-insensitive quinone reductase, EC 1.1.4.2.

Gardill SL and Suttie JW (1990) Vitamin K epoxide and quinone reductase activities. Evidence for reduction by a common enzyme. Biochemical Pharmacology 1055-61. 

Dicoumarol is an artefactual coumarin formed by putrefaction of ensiled sweet clover and has been employed as an anticoagulant because it inhibits quinone reductase activity and, therefore, the function of vitamin K in the way of synthesising coagulation factors. Given that quinones are involved in redox systems affecting mitogenic kinase cascades, dicoumarol was studied for its interaction with some of these enzymes. In fact dicoumarol prevented the activation of SAPK and of nuclear factor-xB (NF-kB) [59]. 

The formation of the 7-carboxyglutamate residues on blood coagulation factors takes place in the hepatocyte before release of the protein. Within the hepatocyte, vitamin K (which is present in the quinone form) is reduced to form vitamin KH2 by a microsomal quinone reductase (see Fig.45.5). Vitamin KH2 is a cofactor for carboxylases that add a carboxyl group to the appropriate glutamate residues in the proenzyme to form the carboxylated proenzyme (e.g., prothrombin). In the same... 

One very active NADHj-cytochrome c reductase from mitochondria recently was separated into two components, a NADHr-ubiquinone reductase and an ubihydroquinone-cytochrome c reductase (see below under Quinone Catalysis ). In addition, non-heme-bound iron was found (about 15 moles/mole of flavin). Martius prepared a highly purified phylloquinone reductase, which contains flavin-adenine dinuoleotide (FAD) and which reduces ubiquinone besides phylloquinone (= vitamin K). The hydroquinone is assumed to be reoxidized to the quinone by cytochrome b. 

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