Monday, April 16, 2007
Dicumarol and Warfarin Inhibit Blood Clotting
Many of the blood coagulation factors are post-translationally modified in various ways. One of these modifications is unusual and it is only seen in these factors and a few other specialized proteins. This modification converts a specific glutamyl side chain to a γ-carboxyglutamyl derivative [Vitamin K].
The carboxylation reaction is catalyzed by vitamin K-dependent carboxylase and it is coupled to the conversion of vitamin K to its oxidized form. In order for the enzyme to modify additional factors, the oxidized form of vitamin K has to be converted back to the reduced form. Recall that vitamin K is an essential vitamin in animals. It can be obtained from plants or from intestinal bacteria.
Recycling of vitamin K is catalyzed by K reductase. The mechanism involves oxidation of two sulfhydryl (-SH groups) to form a disulphide bridge [Disulfide Bridges]. The carboxlase and reductase reactions are required for synthesis of prothrombin, protein C, Protein S, and Factors VII, IX, and X because these proteins must bind C2+ and the γ-carboxyglutamyl group is an excellent cheator of Ca2+.
A vitamin K deficiency means that the carboxylation reaction cannot proceed and this leads to accumulation of inactive clotting factors in the liver. Blood clots cannot form and severe hemorraging can lead to death.
The carboxylation of clotting factors can also be prevented by inhibiting the K reductase reaction. There are many drugs that inhibit this reaction. They are related to warfarin (left) [Monday's Molecule #19]. The best known ones are dicoumarol and coumarin. These drigs, especially warfarin, are used frequently to prevent clotting in patients who have suffered a stroke or otherwise have tendencies to exhibit thrombosis.
Since the drugs prevent synthesis of clotting fators, they take a few days to have an effect. They are usually administerd with heparin, which has an immediate effect on blood clot formation.
Wafarin was a common rat poison in the past since rats are very sensitive to inhibition of K reductase. After eating food laced with wafarin for several days, the rats would die of internal bleeding.