Vitamin K

Vitamin K is a group of 2-methilo-naphthoquinone derivatives.

It is a human vitamin, lipophilic (i.e. soluble in lipids) and therefore hydrophobic (i.e. insoluble in water). It is needed in the synthesis of proteins required for blood coagulation.

Normally it is produced by bacteria in the intestines, and dietary deficiency is extremely rare unless the intestines are heavily damaged.

Vitamin K is involved in the formation of calcium-binding groups in proteins. These calcium-binding groups are called Gla-residues, and the proteins containing these residues are designated as Gla-proteins. The Gla-residues are essential for the biological activity of all Gla-proteins. At this time fewer than 12 human Gla-proteins have been discovered, and they play key roles in the regulation of three physiological processes:

• blood coagulation,
• bone metabolism,
• vascular biology.

Vitamin K-deficiency may occur by disturbed intestinal uptake (such as would occur in a bile duct obstruction), by therapeutic or accidental intake of vitamin K-antagonists or, very rarely, by nutritional vitamin K-deficiency. As a result of the acquired vitamin K-deficiency, Gla-residues are not or incompletely formed and hence the Gla-proteins are inactive. Lack of control of the three processes mentioned above may lead to the following: risk of uncontrolled and massive bleeding, cartilage calcification and severe malformation of developing bone, or deposition of insoluble calcium salts in the arterial vessel walls.

Table of contents

1 Discovery of vitamin K 2 Discovery of Gla-proteins 3 Structures of K-vitamins

Discovery of vitamin K

In the late 1920s, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens with a cholesterol-depleted diet. After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that - together with the cholesterol - a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulations Vitamin.

For several decades the vitamin K-deficient chick model was the only method of quantitating of vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content.

The precise function of vitamin K was not discovered before 1974, when the vitamin K-dependent coagulation factor prothrombin was isolated from cows which had received a high dose of the vitamin K-antagonist warfarin. It was shown that normal prothrombin contained 10 unusual amino acid residues which were identified as g-carboxyglutamate (abbreviation: Gla). Prothrombin isolated from warfarin-treated cows had normal glutamate at the Gla-positions, and was designated as descarboxyprothrombin. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.

Discovery of Gla-proteins

At present, the following human Gla-proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the thrombin-targeting protein Z, the bone Gla-protein osteocalcin, the calcification inhibiting Matrix Gla-protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the proline-rich Gla-proteins (PRGPs) the function of which is at present unknown. In all cases in which their function was known, the presence of the Gla-residues in these proteins turned out to be essential for functional activity.

Gla-proteins occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation was accomplished by Gla-proteins capable of binding to phospholipid membranes and subsequent conversion of procoagulant clotting factors into activated ones.

Another interesting class of invertebrate Gla-proteins is formed by the conantokins, produced by the fish-hunting snail Conus geographus. These snails produce a neurotoxin containing a variety of extremely Gla-rich proteins, which are sufficiently powerful to kill an adult man.

Structures of K-vitamins

Vitamin K is a group name for a number of related compounds, which have in common a methylated naphthoquinone ring structure, and which vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K1) invariably contains in its side chain four isoprenid residues one of which is unsaturated.

Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.

It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.

Figure 1: Chemical structures of vitamin K1 (phylloquinone, left structure) and vitamin K2 (menaquinones, right structure). Both contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain, whereas in menaquinone the side chain is composed of a varying number of isoprenoid residues.

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"Vitamin K" is also a slang term for the chemically and functionally unrelated drug Ketamine.