Vitamin K and metabolic bone disease.

Originally, vitamin K was defined as a factor concerned with haemostasis, deficiency resulting in a haemorrhagic disease. After the initial discovery of phylloquinone in 1929, various compounds were described which all had “vitamin K activity,” that is, the ability to restore normal haemostasis in vitamin K deficient animals. It turned out that “vitamin K” is a group name for several related compounds that are characterised by a common naphthoquinone ring structure substituted with a methyl group at position 2 and an aliphatic side chain at position 3. DiVerences between the various K vitamers consist of variations in the length and degree of saturation of the aliphatic side chain. Phylloquinone (vitamin K-1) has an aliphatic side chain of four prenyl residues, the first of which is unsaturated. In natural menaquinones (vitamin K-2) the number of prenyl residues may vary from 4 to 13, and all are unsaturated. Menaquinones are usually denominated as MK-n, where n stands for the number of prenyl residues. Vitamin K is one of the few vitamins with a precisely known function at the molecular level, and its activity can be tested in vitro using purified enzyme systems, where it serves as a cofactor in the post-translational conversion of protein bound glutamate into a-carboxyglutamate, better known as Gla (fig 1). The reaction is an enzymatic carboxylation reaction, in which the coenzyme vitamin K is oxidised into an epoxide, thus providing the energy to drive this reaction. Vitamin K deficiency thus leads to the synthesis of undercarboxylated proteins. Since Gla residues are calcium binding groups which are essential for the biological activity of the proteins in which they are found, undercarboxylated proteins have a poor aYnity for calcium, and a low biological activity in all cases where their function is known.