| Thrombin |
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| CATEGORIES ABOUT THROMBIN | |
| coagulation system | |
| acute phase proteins | |
| ec 3.4.21 | |
| peripheral membrane proteins | |
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GENERATION Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is post-translationally modified in a Vitamin K -dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the gamma-carboxyglutamic acid residues promote the binding of thrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant Warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade. ACTION Coagulation cascade Thrombin converts fibrinogen to an active form that assembles into fibrin. Thrombin also activates Factor XI , Factor V and Factor VIII . This positive feedback accelerates the production of thrombin. Factor XIII is also activated by thrombin. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Platelets In addition to its activity in the coagulation cascades, thrombin also promotes Platelet activation, via activation of Protease-activated Receptor s on the platelet. Inhibitors and fibrinolysis Thrombin activates Protein C , an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to Thrombomodulin , an integral membrane protein expressed by Endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. ROLE IN DISEASE Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described. An apparently quite common disorder (up to 5% in Western patients) is the substitution of Adenine for Guanine at position 20210 of the prothrombin gene. Although this falls outside the Reading Frame for the protein, it leads to high levels of prothrombin and a possibly increased risk of Thrombosis (Poort ''et al'' 1996). GENE The prothrombin Gene is located on the eleventh Chromosome (11p11-q12). The molecular weight of prothrombin is approximately 72000. Once activated, the catalytic domain of prothrombin (i.e. thrombin, molecular weight 36000) is released from prothrombin fragment 1.2. REFERENCES
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