Peptidase S1A, prothrombin/thrombin <p>In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:</p><ul> <li>Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.</li><li>Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases. </li></ul><p>In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding. </p><p>Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [<cite idref="PUB00003576"/>]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Over 20 families (denoted S1 - S66) of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence [<cite idref="PUB00003576"/>]. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [<cite idref="PUB00003576"/>].</p><p>Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [<cite idref="PUB00003576"/>]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds [<cite idref="PUB00003576"/>]. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [<cite idref="PUB00003576"/>, <cite idref="PUB00000522"/>].</p><p>This group of serine peptidases belong to the MEROPS peptidase family S1, subfamily S1A (chymotrypsin subfamily, clan PA(S)). The type example being chymotrypsin A from <taxon tax_id="9913">Bos taurus</taxon> (Bovine). This group describes both prothrombin and plasminogen-type serine peptidases.</p><p>Prothrombin consists of an N-terminal gamma-carboxyglutamate (GLA) domain, two kringle domains, and the S1A peptidase catalytic domain. The cleavage of prothrombin to thrombin is catalysed by the prothrombinase enzyme complex that consists of serine protease factor Xa, cofactor Va, phospholipids and calcium. Prothromin is cleaved by this enzyme into three fragments: fragment 1 (F1) consits of the GLA domain and the first Kringle domain; fragment 2 (F2) consists of the second Kringle domain; and thrombin (peptidase catalytic domain). F1 facilitates calcium-dependent binding of the proenzyme to phospholipid surfaces. F2 interacts with factor Va, and once it is released from prothrombin, it can bind thrombin to influence its function [<cite idref="PUB00017186"/>].</p><p>Thrombin is a member of the trypsin family of S1 peptidases. It catalyses the preferential cleavage of arginine-lysine bonds, converting fibrinogen to fibrin, and releasing fibrinopeptides A and B. Thrombin can itself cleave the N-terminal fragment (fragment 1) of prothrombin, prior to its activation by factor Xa. Its effects are mediated by the thrombin receptor. Structures of the thrombin A-chain [<cite idref="PUB00008317"/>] and B-chain [<cite idref="PUB00008318"/>] have been determined. The most conserved portions of the B chain are the active-site residues and adjacent amino acids, the B loop, and the primary substrate-binding region [<cite idref="PUB00008319"/>]. The extent of sequence similarity between species and the conservation of many of the functional/structural motifs suggests that, in addition to their role in blood coagulation, vertebrate thrombins may play an important role in the general mechanisms of wound repair [<cite idref="PUB00008319"/>].</p><p>The activation of the fibrinolytic system depends upon the cleavage of plasminogen into the serine protease plasmin by the urokinase-type or tissue-type plasminogen activators [<cite idref="PUB00017187"/>]. Plasmin acts to degrade fibrin at specific residues, as well as binding to a variety of other proteins, including fibronectin, albumin, thrombospondin, von Willebrand factor, fibulin, fibroblast growth factor-2, vascular endothelial growth factor, and interleukin-1 [<cite idref="PUB00017188"/>].</p>