Cascade, blood clotting

FIGURE 18.40 The glutamyl carboxylase reaction is vitamin K-dependent. This enzyme activity is essential for the formation of 7-car-boxyglutamyl residues in several proteins of the blood-clotting cascade (Figure 15.5), accounting for the vitamin K dependence of coagulation. 

Ionized calcium is an important regulator of a variety of cellular processes, including muscle contraction, stimulus-secretion coupling, the blood clotting cascade, enzyme activity, and membrane excitability. It is also an intracellular messenger of hormone action. 

A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of a-ketoglutarate (Figure 28-11). Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and prohne hydroxylase is also required in formation of osteocalcin and the Clq component of complement. Aspartate P-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease which hydrolyzes activated factor V in the blood clotting cascade. TrimethyUysine and y-butyrobetaine hydroxylases are required for the synthesis of carnitine. 

Although the final steps of the blood clotting cascade are identical, the initial steps can occur via two distinct pathways extrinsic and intrinsic. Both pathways are initiated when specific clotting proteins make contact with specific surface molecules exposed only upon damage to a blood vessel. Clotting occurs much more rapidly when initiated via the extrinsic pathway. 

Figure 3.1 Principal protein amino acid side-chain metal-ion binding modes (the metal ion represented as a dark filled circle) and (right) the structure of the Ca2+-binding y-carboxyglutamate found in proteins of the blood-clotting cascade.

The catalytic mechanism of the subtilisins is the same as that of the digestive enzymes trypsin and chymotrypsin as well as that of enzymes in the blood clotting cascade, reproduction and other mammalian enzymes. The enzymes are known as serine proteases due to the serine residue which is crucial for catalysis (Kraut, 1977 and Polgar, 1987)... 

In apoptosis a series of events takes place in an orderly sequence involving the activation of various proteases which are called caspases, for cysteine and aspartate proteases. Several distinct caspases act in a cascade vaguely reminiscent of the blood-clotting cascade of complement proteins. If one wishes to interfere with the apoptotic process, then one strategy would be to develop drugs that inhibit various caspases, a current effort underway in the pharmaceutical industry. 

Such an intermediate is known to be formed in reactions catalyzed by trypsin, chymotrypsin, thrombin, other enzymes of the blood-clotting cascade (except angiotensinconverting enzyme, which is an aspartic protease). An acyl-serine intermediate is also formed in the acetylcholinesterase reaction. The active site serine of this enzyme and the serine proteases can be alkylated by diisopropyl-fluorophosphate. See also Active Site Titration... 

Factor VIII (FVIII) is an essential coagulation factor in the blood which serves as a cofactor in the complex blood-clotting cascade. A deficiency in FVIII is the... 

Complement - A network of proteins known as complement also contribute to the process in a manner somewhat analogous to the blood clotting cascade. The difference is that this cascade destroys nonself. 

From study of peptides formed by partial hydrolysis of the 32P-labeled chymotrypsin, the sequence of amino acids surrounding the reactive serine was established and serine 195 was identified as the residue whose side chain hydroxyl group became phosphorylated. The same sequence Gly-Asp-Ser-Gly was soon discovered around reactive serine residues in trypsin, thrombin, elastase, and in the trypsin-like cocoonase used by silkmoths to escape from their cocoons.198 We know now that these are only a few of the enzymes in a very large family of serine proteases, most of which have related active site sequences.199 200 Among these are thrombin and other enzymes of the blood-clotting cascade (Fig. 12-17), proteases of lysosomes, and secreted proteases. 

Figure 12-17 Major components of the human blood clotting cascades. The site of action of the leech anticoagulant protein hirudin is also indicated.

Proteolytic conversion of inactive zymogens to active enzymes was noted in Chapter 5. Other examples of posttranslational proteolytic cleavages include the conversions of proalbumin to albumin (Chapter 7), of preprocollagen to collagen (Chapter 8), and of preproinsulin to insulin (Chapter 16) and the activation of the compounds of the blood-clotting cascade (Chapter 7). 

As is the case with some chemical changes occurring in biological systems, such as the blood-clotting cascade system, deteriorative reactions considered to have a beneficial effect are found in foods. For example, the Maillard reaction (lJ7,lj3) is used to produce flavors and colors in such foods as beverages and baked goods. Heat treatment (involving denaturation) has been found to increase the nutritional value of raw soybean meal by... 

Figure 5.3. Intrinsic and extrinsic blood clotting cascades. Factor I, fibrinogen Factor II, prothrombin (vitamin K-dependent) Factor III, thromboplastin Factor V, proac-celerin Factor VII, proconvertin (vitamin K-dependent) Factor VIII, antihemophilic factor Factor IX, Christmas factor (vitamin K-dependent) Factor X, Stnart factor (vitamin K-dependent) Factor XI, plasma thromboplastin Factor XII, Hageman factor Factor XIII, fibrin-stabilizing factor and Factor XIV, protein C (vitamin K-dependent). What was at one time called Factor IV is calcinm no factor has been assigned nnmber VI.

Figure 10.37. Blood-Clotting Cascade. A fibrin clot is formed by the interplay of the intrinsic, extrinsic, and final common pathways. The intrinsic pathway begins with the activation of factor XII (Hageman factor) by contact with abnormal surfaces produced by injury. The extrinsic pathway is triggered by trauma, which activates factor VII and releases a lipoprotein, called tissue factor, from blood vessels. Inactive forms of clotting factors are shown in red their activated counterparts (indicated by the subscript "a") are in yellow. Stimulatory proteins that are not themselves enzymes are shovm in blue. A striking feature of this process is that the activated form of one clotting factor catalyzes the activation of the next factor.

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