Vitamin K hydroquinone

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... 

In the case of ubiquinones we have already considered the ability of quinones to react with superoxide and other free radicals. Naphthoquinones, vitamin K and its derivatives, especially menadione, are the well known producers of superoxide through redox cycling with dioxygen. However, in 1985, Canfield et al. [254] have shown that vitamin K quinone reduced the oxidation of linoleic acid while vitamin K hydroquinone stimulated lipid peroxidation. Surprisingly, later on, conflicting results were reported by Vervoort et al. [255] who found that only hydroquinones of vitamin K and its analogs inhibited microsomal lipid peroxidation. 

I. 1.4.1] catalyzes the reaction of 2-methyl-3-phytyl-l,4-naphthoquinone 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 vitamin K and possibly to vitamin K hydroquinone by 1,4-dithioer-ythritol (which is oxidized to the disulfide). Some other dithiols and butane-4-thiol can also act as substrates. This enzyme is strongly inhibited by warfarin. 

The oxidation of vitamin K hydroquinone monoanion (17) with labelled, 802 in THF leads to vitamin K oxide (18) in which the epoxide oxygen is fully labelled, hi addition, partial incorporation of 180 at the carbonyl oxygen is observed (on the basis of the mass spectrum).215 This is most readily explained by invoking a dioxetane intermediate (19) as opposed to the alternative intermediacy of a 2-hydroperoxide (20), where only the epoxide oxygen would be expected to be labelled. 

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). 

Silver oxide is the reagent of choice for oxidation of vitamin K, hydroquinone, because this substance is readily soluble in ether and because the conversion is quantitative evaporation of the filtered solution gives analytically pure K, a yellow oil. Tn this case commercial reagent is satisfactory. 

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). 

II). These vitamin K antagonists are used therapeutically as anticoagulants, because they block conversion of the vitamin K epoxide back to the vitamin K hydroquinone (Fig. 4.2). 

Figure 3 Vitamin K oxidalion-reduclion ( de during Gla formation. Oxidation of vitamin K hydroquinone (reduced vitamin) to vitamin K epoxide by molecular oxygen provides the energy needed to drive the carboxylation of peptidyl-Glu to pepddyl-Gla (i.e., gamma-carboxy glutamate). The vitamin K epoxide is then recycled by reduction with dithiols in two stages. The first stage requires a reductase enzyme that is coumarin drug (e.g., warfarin) inhibitable. The second stage can be catalyzed by either of two reductases, one of which is NAD(P)H dependent and is not warfarin inhibited.

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