Blood-clotting proteins

Vitamin K A cofactor for the carboxylase of the hepatic endoplasmic reticulum, which is responsible for completing the synthesis of blood-clotting proteins. 

VITAMIN K IS REQUIRED FOR SYNTHESIS OF BLOOD-CLOTTING PROTEINS... 

Prothrombin and several other proteins of the blood clotting system (Factors VII, IX and X, and proteins C and S) each contain between four and six y-carboxygluta-mate residues which chelate calcium ions and so permit the binding of the blood clotting proteins to membranes. In vitamin K deficiency or in the presence of warfarin, an abnormal precursor of prothrombin (preprothrombin) containing little or no y-carboxyglutamate, and incapable of chelating calcium, is released into the circulation. 

Vermeer, C. (1990) y-Carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem. J. 266, 625-636. Describes the biochemical basis for the requirement of vitamin K in blood clotting and the importance of carboxylation in the synthesis of the blood-clotting protein thrombin. 

Extra carboxyl groups may be added to Glu residues of some proteins. For example, the blood-clotting protein prothrombin contains a number of y-carboxygluta-mate residues (Fig. 27-29b) in its amino-terminal region, introduced by an enzyme that requires vitamin K. These carboxyl groups bind Ca2+, which is required to initiate the clotting mechanism. 

Other covalent modifications These may be required for the functional activity of a protein. For example, additional carboxyl groups can be added to glutamate residues by vitamin Independent carboxylation (see p. 387). The resulting y-carboxy-glutamate resides are esssential for the activity of several of the blood-clotting proteins. Attachment of lipids, such as farnesyl groups, can help anchor proteins in membranes. In addition, many proteins are acetylated postranslationally. 

A protein called Stuart factor cleaves prothrombin, turning it into active thrombin that can then cleave fibrinogen to fibrin to form the blood clot.3 Unfortunately, as you may have guessed, if Stuart factor, prothrombin, and fibrinogen were the only blood-clotting proteins, then Stuart factor would rapidly trigger the cascade, congealing all... 

Limentani SA, Roth DA, Furie BC, Furie B. Recombinant blood clotting proteins for hemophiha therapy. Semin Throm Hemost 1993 19 62-72. 

Blood-clotting tests. Since the liver synthesises many of the blood-clotting proteins, bloodclotting tests may be used as a marker of the severity of certain liver disorders. 

The major function of the K vitamins is in the maintenance of normal levels of the blood clotting proteins, factors II, VII, IX, X and protein C and protein S, which are synthesized in the liver as inactive precursor proteins. Conversion from inactive to active clotting factor requires a post-translational modification of specific glutamate (E) residues. This modification is a carboxylation and the enzyme responsible for it requires vitamin K as a cofactor. 

Vitamin K status can be assessed by a functional test, called the "prothrombin time test," which involves measuring the lime required to form a blood clot. The test is performed as follows. A blood sample is withdrawn from a subject and immediately mixed with citric acid. Citric acid is a chelator, which means that it can form a tight complex with ions, such as calcium ions. The chelator prevents the interaction of calcium ions with the blood-clotting proteins and thus prevents these proteins from forming a blood clot in the sample. Calcium ions, it should be noted, are required for supporting the activity of several blood clotting proteins. The "citrated blood" is placed in a machine called a fibrometer. The fibrometer is used to detect increases in the viscosity of the blood over a period. 

Figure 1.20 depicts an available next step of the sequence, where the step leads to secretion into the extracellular fluid. Polypeptides of this type include albumin, polypeptide hormones, blood clotting proteins, lipoproteins, and antibodies. 

Fig. 11.4 Mechanism of clotting factor localization to an activated platelet surface. Left After synthesis in the liver, certain blood clotting proteins are posttranslationally modified in the endoplasmic reticulum by a vitamin K-dependent Vit K carboxylase. This enzyme forms carboxyglutamate residues (top center) that chelate calcium ions. Right In the bloodstream, clotting factor-bound calcium ions attach to negatively charged phosphatidylserine that appears on the surface of activated platelets. Certain therapeutic drugs or acquired deficiencies inhibit this process - see text (Original figure submitted by Dr Paul DeAngelis, Department of Biochemistry, University of Oklahoma HSC, Oklahoma City, OK, USA)...

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