Vitamin K was discovered as a result of investigations into the cause of a bleeding disorder, hemorrhagic (sweet clover) disease of cattle and of chickens fed on a fat-free diet. The missing factor in the diet of the chickens was vitamin K, while the cattle feed contained dicumarol, an antagonist of the vitamin. Antagonists of vitamin K are used to reduce blood coagulation in patients at risk of thrombosis; the most widely used is warfarin.

Three compounds have the biological activity of vitamin K (Figure 1): phylloquinone, the normal dietary source, found in green vegetables; menaquinones, synthesized by intestinal bacteria, with differing lengths of side chain; and menadione and menadiol diacetate, synthetic compounds that can be metabolized to phylloquinone. Menaquinones are absorbed to some extent, but it is not clear to what extent they are biologically active as it is possible to induce signs of vitamin K deficiency simply by feeding a phylloquinone deficient diet, without inhibiting intestinal bacterial action.

Fig1. The vitamin K vitamers. Menadiol (or menadione) and menadiol diacetate are synthetic compounds that are converted to menaquinone in the liver.

Vitamin K Is the Coenzyme for Carboxylation of Glutamate in Postsynthetic Modification of Calcium-Binding Proteins

Vitamin K is the cofactor for the carboxylation of glutamate residues in the postsynthetic modification of proteins to form the unusual amino acid γ-carboxyglutamate (GLA) (Figure 2). Initially, vitamin K hydroquinone is oxidized to the epoxide, which activates a glutamate residue in the protein substrate to a carbanion, which reacts nonenzymically with carbon dioxide to form γ-carboxyglutamate. 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 quinone reductase. In the presence of warfarin, vitamin K epoxide cannot be reduced, but accumulates and is excreted. If enough vitamin K (as the quinone) is provided in the diet, it can be reduced to the active hydroquinone by the warfarin-insensitive enzyme, and carboxylation can continue, with stoichiometric utilization of vitamin K and excretion of the epoxide. A high dose of vitamin K is the antidote to an overdose of warfarin.

Fig2. The role of vitamin K in the synthesis of γ-carboxyglutamate.

Prothrombin and several other proteins of the blood clotting system (factors VII, IX, and X, and proteins C and S) each contain 4 to 6 γ-carboxyglutamate residues. γ-Carboxyglutamate chelates calcium ions, and so permits the binding of the blood-clotting proteins to membranes. In vitamin K deficiency, or in the presence of warfarin, an abnormal precursor of prothrombin (preprothrombin) containing little or no γ-carboxyglutamate, and incapable of chelating calcium, is released into the circulation.

Vitamin K Is Also Important in Synthesis of Bone & Other Calcium-Binding Proteins

A number of other proteins undergo the same vitamin K dependent carboxylation of glutamate to γ-carboxyglutamate, including osteocalcin and the matrix Gla protein in bone, nephrocalcin in kidney and the product of the growth arrest specific gene Gas6, which is involved in both the regulation of differentiation and development in the nervous system, and control of apoptosis in other tissues. All of these γ-carboxyglutamate–containing proteins bind calcium, which causes a conformational change so that they interact with membrane phospholipids. The release into the circulation of osteocalcin provides an index of vitamin D status.

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مواضيع ذات صلة

Water is an Excellent Nucleophile

Interaction with Water Influences the Structure of Biomolecules

Fibrin Clots Are Dissolved by Plasmin

The Activity of Antithrombin, an Inhibitor of Thrombin, Is Increased by Heparin

Conversion of Fibrinogen to Fibrin Is Catalyzed by Thrombin

Factor Xa Leads to Activation of Prothrombin to Thrombin

Most Transmembrane Proteins Have Membrane Spanning α Helices

Lipid Composition Is Different in the Exoplasmic and Cytosolic Leaflets

Lipid Composition Influences the Physical Properties of Membranes

The Intrinsic Pathway Also Leads to Activation of Factor X

The Extrinsic Pathway Leads to Activation of Factor X

Both Extrinsic & Intrinsic Coagulation Pathways Result in the Formation of Fibrin