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.
4 comments :
Very informative, thanks!
Where did "warfarin" get its name? When I first met it (in a package of rat poison), my first thought was that it was somehow related to a poison used in warfare, like Mustard gas, hence "warfare-in". But I've since heard that this is not the case, and the name is based on some sequence of naming of new products at the company where it was developed.
Years ago, when I first met warfarin, I was living in a small basement suite in a house. My landlord gave me some to deal with a mouse that was living somewhere in my kitchen, that I had named "Sputnik" in hopes of capturing and launching it into orbit.
Warfarin did not kill the mouse. The only noticeable change was the colour of the droppings - they turned from black to light brown. Are mice more tolerant of warfarin's effects than are rats?
I'm pretty sure we've killed mice with warfarin -- although that may be because the mouse, while missing the set-out baits, managed to get in to the stored box of poison itself and ate a whole big chunk of it! Stupid mouse.
When my father was on warfarin, he used to joke about taking rat poison.
blood clot are semi-solid masses of sticky blood cells that form when a blood vessel is damaged. The body creates blood clots as a normal response to blood ...
Warfarin is actually an analog of Dicoumarol, a substance found in spoiled clover hay that caused hemorrhages in cattle. The name Warfarin comes from the group that discovered it. The Wisconsin Alumni, Research, Foundation, and then they added the "arin" as it's the suffix to this class of anticoagulants. Warfarin will kill mice, (it will kill humans if given a large enough dose), because mice do not have the ability to vomit. Once ingested the mouse basically bleeds to death on the inside. The trick is to get them to eat a large enough amount to kill them.
Post a Comment