Biological Role of Vitamin K

The Vitamin K Epoxide Cycle

FAO/WHO 

Vitamin K is an essential fat-soluble micronutrient which is needed for a unique post-translational chemical modification in a small group of proteins with calcium-binding properties, collectively known as vitamin K – dependent proteins or Gla-proteins. Thus far, the only unequivocal role of vitamin K in health is in the maintenance of normal coagulation.

The vitamin K – dependent coagulation proteins are synthesised in the liver and comprise factors II, VII, IX, and X, which have a haemostatic role (i.e., they are procoagulants that arrest and prevent bleeding), and proteins C and S, which have an anticoagulant role (i.e., they inhibit the clotting process). 

Despite this duality of function, the overriding effect of nutritional vitamin K deficiency is to tip the balance in coagulation towards a bleeding tendency caused by the relative inactivity of the procoagulant proteins. Vitamin K – dependent proteins synthesised by other tissues include the bone protein osteocalcin and matrix Gla protein; their functions remain to be clarified.

Biological role of vitamin K

Vitamin K is the family name for a series of fat-soluble compounds, which have a common 2-methyl-1, 4-naphthoquinone nucleus but differ in the structures of a side chain at the 3-position. They are synthesised by plants and bacteria. In plants the only important molecular form is phylloquinone (vitamin K1), which has a phytyl side chain. Bacteria synthesise a family of compounds called menaquinones (vitamin K2), which have side chains based on repeating unsaturated 5-carbon (prenyl) units. 

These are designated menaquinone-n (MK-n) according to the number (n) of prenyl units. Some bacteria also synthesise menaquinones in which one or more of the double bonds is saturated. The compound 2-methyl-1,4-naphthoquinone (common name menadione) may be regarded as a provitamin because vertebrates can convert it to MK-4 by adding a 4-prenyl side chain at the 3-position.

Suttie, J.W. 1985. Vitamin K. 1985. In: Fat-soluble vitamins: their biochemistry and

applications. Diplock, A.D., ed. p. 225-311. London: Heinemann.

Furie, B. & Furie, B.C. 1990. Molecular basis of vitamin K-dependent γ-carboxylation.

Blood, 75: 1753-62.

The biologic role of vitamin K is to act as a cofactor for a specific carboxylation reaction that transforms selective glutamate (Glu) residues to γ-carboxyglutamate (Gla) residues. The reaction is catalysed by a microsomal enzyme, γ-glutamyl, or vitamin K – dependent carboxylase, which in turn is linked to a cyclic salvage pathway known as the vitamin K epoxide cycle (Figure 11). 

Scheme shows the cyclic metabolism of vitamin K in relation to the conversion of glutamate (Glu) to γ-carboxyglutamate (Gla) residues for the coagulation protein prothrombin. A general term for the glutamate precursors of vitamin K-dependent proteins is proteins induced by vitamin K absence, abbreviated PIVKA. For prothrombin (factor II) the glutamate precursor is known as PIVKA-II. 

The active form of vitamin K needed for carboxylation is the reduced form, vitamin K quinol. Known enzyme reactions are numbered 1, 2, and 3. The carboxylation reaction is driven by a vitamin K-dependent carboxylase activity (reaction 1) which simultaneously converts vitamin K quinol to vitamin K 2,3-epoxide. Vitamin K 2,3- epoxide is reduced back to the quinone and then to the quinol by vitamin K epoxide reductase (reaction 2). 

The reductase activity denoted 2 is dithiol dependent and is inhibited by coumarin anticoagulants such as warfarin. Dietary vitamin K may enter the cycle via an NAD(P)H-dependent vitamin K reductase activity (reaction 3), which is not inhibited by warfarin.

Suttie, J.W. 1985. Vitamin K. 1985. In: Fat-soluble vitamins: their biochemistry and applications. Diplock, A.D., ed. p. 225-311. London: Heinemann.

Furie, B. & Furie, B.C. 1990. Molecular basis of vitamin K-dependent γ-carboxylation. Blood, 75: 1753-62.

Davie, E.W. 1995. Biochemical and molecular aspects of the coagulation cascade. Thromb. Haemost., 74: 1-6. 

The four vitamin K-dependent procoagulants (factor II or prothrombin, and factors VII, IX, and X) are serine proteases that are synthesised in the liver and then secreted into the circulation as inactive forms (zymogens). Their biologic activity depends on their normal complement of Gla residues, which are efficient chelators of calcium ions. 

In the presence of Gla and calcium ions these proteins bind to the surface membrane phospholipids of platelets and endothelial cells where, together with other cofactors, they form membrane-bound enzyme complexes. When coagulation is initiated, the zymogens of the four vitamin Kdependent clotting factors are cleaved to yield the active protease clotting factors. 

Two other vitamin K-dependent proteins called protein C and protein S play a regulatory role in the inhibition of coagulation. The function of protein C is to degrade phospholipid-bound activated factors V and VIII in the presence of calcium. Protein S acts as a synergistic cofactor to protein C by enhancing the binding of activated protein C to negatively charged phospholipids. Yet another vitamin K-dependent plasma protein (protein Z) is suspected to have a haemostatic role but its function is currently unknown. 

Vermeer, C. 1990. γ-Carboxyglutamate-containing proteins and the vitamin K-dependent

carboxylase. Biochem. J., 266: 625-36.

Ferland, G. 1998. The vitamin K-dependent proteins: an update. Nutr. Revs., 56: 223-30.

Apart from the coagulation proteins, several other vitamin K-dependent proteins havebeen isolated from bone, cartilage, kidney, lungs, and other tissues.

Luo, G. 1997. Spontaneous calcification of arteries and cartilage in mice lacking matrix  GLA protein. Nature, 386: 78-81.

Only two, osteocalcin and matrix Gla protein (MGP), have been well characterised. Both are found in bone but MGP also occurs in cartilage, blood vessel walls, and other soft tissues. There is evidence that protein S is synthesised by several tissues including the vessel wall and bone and may have other functions besides its well-established role as a coagulation inhibitor. It also seems likely that one function of MGP is to inhibit mineralisation.

Vermeer, C., Jie, K.S. & Knapen, MHJ. 1995. Role of vitamin K in bone metabolism. Ann. Rev. Nutr., 15: 1-22.

Binkley, N.C. & Suttie, J.W. 1995. Vitamin K nutrition and osteoporosis. J. Nutr., 125:

1812-21.

Shearer, M.J. 1997. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc. Nutr. Soc., 56: 915-37.

Thus far, no clear biologic role for osteocalcin has been established despite its being the major non-collagenous bone protein synthesised by osteoblasts. This failure to establish a biologic function for osteocalcin has hampered studies of the possible detrimental effects of vitamin K deficiency on bone health. Evidence of a possible association of a suboptimal vitamin K status with increased fracture risk remains to be confirmed.