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Vitamin K represents a group of lipophilic and hydrophobic vitamins.


Three compounds have the biological activity of vitamin K, phylloquinone (Vitamin K1), the normal dietary source, found in green vegetables; menaquinones (vitamin K2), synthesized by intestinal bacteria, with differing lengths of side chain; and menadione and menadiol diacetate, synthetic compounds that can be metabolized to phylloquinone.

 Structure of vitamin K

Figure-1- Vitamin K family are naphtoquinone derivatives . Phylloquinones and menaquinones, both have a long isoprenoid side chain. The length of the side chain differs. Phylloquinonse have a  20 C side chain , whereas menaquinones have a 30 C side chain. The isoprenoid chain makes these vitamin hydrophobic or lipophilic. The synthetic vitamin K (menadione, menadiol diacetate) have only hydrogen in place of isoprenoid side chain that makes these vitamin water-soluble.

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.

Dietary Sources

Vitamin K is found in green leafy vegetables such as kale and spinach, and appreciable amounts are also present in margarine and liver. Vitamin K is present in vegetable oils and is particularly rich in olive, canola, and soybean oils.

Absorption and Storage

Absorption takes place in intestine in the presence of bile salts. The transportation from intestine is carried out through chylomicrons. Storage occurs in liver and from liver transportation to peripheral cells is carried out bound with beta lipoproteins.

Clinical significance

Fat malabsorption is associated with impaired absorption of vitamin K and other fat soluble vitamins. Vitamin K is important for the coagulation process. In its deficiency coagulation process is grossly affected resulting in tendency for bleeding and hemorrhages. Absorption of vitamin K may also be decreased by mineral oil, bile acid sequestrants (Cholestyramine, colestipol) and Orlistat (weight loss medication).

Recommended daily allowance

The average daily allowance is 50-100 mg/day.

Functions of vitamin K

Vitamin K Is the coenzyme for carboxylation of Glutamate in post synthetic modification of calcium binding proteins

The only known biological role of vitamin K is as a cofactor for an enzyme (Carboxylase) that catalyzes the carboxylation of the amino acid, glutamic acid, resulting in its conversion to gamma-carboxy glutamic acid (Gla). Although vitamin K-dependent gamma-carboxylation occurs only on specific glutamic acid residues in a small number of vitamin K-dependent proteins, it is critical to the calcium-binding function of those proteins.

Calcium binding proteins

Vitamin K–dependent proteins are a heterogeneous group, including clotting factor proteins and also proteins found in bone, lung, kidney, and placenta.

1) Role of vitamin K in coagulation

The ability to bind calcium ions (Ca2+) is acquired by the activation of the  vitamin K-dependent clotting factors, or proteins, in the coagulation cascade. Factors II (prothrombin), VII, IX, and X make up the core of the coagulation cascade. These factors are synthesized in the liver in the inactive form. They undergo post translational modifications, gamma carboxylation of glutamic acid residues. This process of  gamma carboxylation of glutamic acid residues imparts another negative charge, so as to promote the effective binding of these factors/proteins to calcium ions.

Vitamin K cycle

Although vitamin K is a fat-soluble vitamin, the body stores very little of it, and its stores are rapidly depleted without regular dietary intake. Perhaps, because of its limited ability to store vitamin K, the body recycles it through a process called the vitamin K cycle. The vitamin K cycle allows a small amount of vitamin K to function in the gamma-carboxylation of proteins many times, decreasing the dietary requirement.

Vitamin K hydroquinone (active form) is oxidized to the epoxide form during the process of enzymatic reaction.The initial form (hydroquinone form) is regenerated by two steps process. Vitamin K epoxide is reduced to the quinone by a epoxide reductase, and the quinone is reduced to the active hydroquinone by either the same reductase or by a vitamin K reductase(quinone reductase).(Figure-2)

 Vitamin K cycle

Figure-2-  Role of vitamin K in the gamma carboxylation of glutamate residues of various proteins. The arrow shows the site of action of warfarin. Reduced lipoamide is required for the activity of epoxide reductase whereas NADPH is needed for the action of vitamin K reductase.

Prothrombin and several other proteins of the blood clotting system (Factors VII, IX, and X, and proteins C and S) each contain 4–6 γ-carboxyglutamate residues. γ-Carboxyglutamate chelates calcium ions, and so permits the binding of the blood clotting proteins to membranes.

Vitamin K Antagonists

Some oral anticoagulants, such as Dicumarol and warfarin, inhibit coagulation through antagonism of the action of vitamin K. Warfarin prevents the recycling of vitamin K by inhibiting two important reactions and creating a functional vitamin K deficiency (figure-2).

Warfarin is a competitive inhibitor of epoxide reductase. In the presence of warfarin, vitamin K epoxides cannot be reduced, they accumulate and are excreted. As a result, abnormal precursor of prothrombin (preprothrombin) containing little or no carboxyglutamate, and incapable of chelating calcium, is released into the circulation. Thus, in the presence of warfarin or in vitamin K deficiency the process of coagulation is inhibited,

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 (Vitamin K reductase) and carboxylation can continue, with stoichiometric utilization of vitamin K and excretion of the epoxide. Thus a high dose of vitamin K is the antidote to an overdose of warfarin.

Large quantities of dietary or supplemental vitamin K can overcome the anticoagulant effect of vitamin K antagonists, so patients taking these drugs are cautioned against consuming very large or highly variable quantities of vitamin K in their diets.

Like all anticoagulants, the major side effect of warfarin is bleeding. A rare complication is skin necrosis. Warfarin crosses the placenta and can cause fetal abnormalities. Treatment of pregnant women with warfarin can lead to fetal bone abnormalities (Fetal Warfarin syndrome). Consequently, warfarin should not be used during pregnancy.

 2) Vitamin K Is Also Important in Synthesis of Bone Calcium-Binding Proteins

Two proteins that contain γ-carboxyglutamate are present in bone, osteocalcin, and bone matrix Gla protein.

Osteocalcin is a protein synthesized by osteoblasts. The synthesis of osteocalcin by osteoblasts is regulated by the active form of vitamin D, 1,25(OH)2D3 or calcitriol. The mineral-binding capacity of osteocalcin requires vitamin K-dependent gamma-carboxylation of three glutamic acid residues. The function of osteocalcin is unclear but is thought to be related to bone mineralization. After gamma carboxylation osteocalcein binds tightly to calcium. Osteocalcin also contains hydroxyproline, so its synthesis is dependent on both vitamins K and C; in addition, its synthesis is induced by vitamin D. The release into the circulation of osteocalcin provides an index of vitamin D status.

Matrix Gla protein- MGP has been found in bone, cartilage, and soft tissue, including blood vessels. MGP prevents the calcification of soft tissues and cartilages, while facilitating normal bone growth and development.

Protein S- The vitamin K-dependent anticoagulant protein S is also synthesized by osteoblasts, but its role in bone metabolism is unclear. Children with inherited protein S deficiency suffer complications related to increased blood clotting as well as decreased bone density.



 Role of vitamin K (Summary)

Figure-3- vitamin K cycle and the role of vitamin K in post synthetic modification of calcium binding proteins.

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