Thrombin, serine function

Coagulation Factors II, III, VII, IX, X, XI, and Xlla fragments, thrombin, and plasmin are classified as serine proteases because each possesses a serine residue with neighboring histidine and asparagine residues at its enzymatically active site (Table 3). Factors II, VII, IX, and X, Protein C, Protein S, and Protein Z are dependent on the presence of vitamin K [84-80-0] for their formation as biologically functionally active procoagulant glycoproteins. 

The serine proteases are the most extensively studied class of enzymes. These enzymes are characterized by the presence of a unique serine amino acid. Two major evolutionary families are presented in this class. The bacterial protease subtilisin and the trypsin family, which includes the enzymes trypsin, chymotrypsin, elastase as well as thrombin, plasmin, and others involved in a diverse range of cellular functions including digestion, blood clotting, hormone production, and complement activation. The trypsin family catalyzes the reaction ... 

Gingrich, M.B., et al. 2000. Potentiation of NMDA receptor function by the serine protese thrombin. J Neurosci 20 4582. 

Heparin acts by binding to anti thrombin III, which serves as a major inhibitor of serine protease clotting enzymes. Abruptly ending heparin treatment can be hazardous because of reduced levels of antithrombin III. Coumarins, typified by warfarin, are structurally similar to vitamin K, which plays an important role in blood coagulation. By interfering with the function of vitamin K, vitamin K-dependent proteins such as clotting factors VII, IX, X and prothrombin are reduced. 

Compound 165 and its derivatives inhibit serine protease enzymes such as TF/factor Vila and Xa (tissue factor) <2004USP0235852>. Benzofurans 166 and 167, which have transposed functional groups, are both TF/factor X inhibitors. Tissue factors are involved in the release of thrombin, so these compounds are applied to the treatment of clotting disorders <2003W003082847, 2005JPP2005120080>. Diarylbenzofuran 168 is used to inhibit bone loss <1996USP5489587>. 

Enzyme which can hydrolyse the sericin is classified as proteolytic enzymes [63-65]. The proteolytic enzymes cleave the peptide/amide linkages and convert them into amino acid. Mainly there are three types of proteolytic enzymes such as zinc protease (e.g. carboxy peptidase A), serine protease (Chymotrypsin, Trypsin, Thrombin) and thiol protease (acts as cystine residue in the protein). The function of proteolytic enzymes in their degree of degumming depends on the pH of the bath and the optimum activity is found to be different at different pH for different enzymes. 

The first principle of enzyme inhibitor design is Use aU the available information . This information can be biological, functional, structural, chemical, or theoretical. There is such an immense amount of biological information on thrombin that it cannot be surveyed here we focus on thrombin as a serine protease of the trypsin family and take fibrinogen to be its primary substrate. A convenient way to look at the information available is from the more general to the very specific. For thrombin, we may take four levels the general catalytic mechanism the particular substrate types processed the structure of the protein and, often forgotten, the flexibihty of the protein required to achieve this function. 

Many research groups have started with PPACK and produced inhibitors of a less peptidic nature (to improve in vivo stabihty), and/or with conformational restriction (to tackle the entropy loss problem), and/or with a variety of serine trap functionalities, for example, aldehydes, boronic acids, a-keto amides and acids, a-keto heterocycles, polyfluorinated ketones, and phosphonates. Structures of many of these are known in complex with thrombin but will not be reviewed here (see e.g., pubhca-tions of C.A. Kettner and coworkers). As well as lack of specificity, these potential drugs suffer from slow on-rates and have not progressed to the market. 

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