Peptidase S8/S53, subtilisin/kexin/sedolisin <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 families S8 (subfamilies S8A (subtilisin) and S8B (kexin)) and S53 (sedolisin) both of which are members of clan SB.</p><p>The subtilisin family is the second largest serine protease family characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence [<cite idref="PUB00006225"/>]. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses [<cite idref="PUB00003576"/>]. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [<cite idref="PUB00003576"/>, <cite idref="PUB00000522"/>]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [<cite idref="PUB00003576"/>, <cite idref="PUB00000522"/>]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [<cite idref="PUB00003576"/>]. Based on sequence homology, a subdivision into six families has been proposed [<cite idref="PUB00006225"/>]. </p><p>The proprotein-processing endopeptidases kexin, furin and related enzymesform a distinct subfamily known as the kexin subfamily (S8B). These preferentiallycleave C-terminally to paired basic amino acids. Members of this subfamilycan be identified by subtly different motifs around the active site [<cite idref="PUB00003576"/>, <cite idref="PUB00000522"/>].Members of the kexin family, along with endopeptidases R, T and K from theyeast Tritirachium and cuticle-degrading peptidase from Metarhizium, requirethiol activation. This can be attributed to the presence of Cys-173 near tothe active histidine [<cite idref="PUB00000522"/>].Only 1 viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish [<cite idref="PUB00003576"/>]. </p><p>Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from <taxon tax_id="33067">Pseudomonas sp. 101</taxon>, as well as for kumamolisin from a thermophilic bacterium, <taxon tax_id="198803">Bacillus sp. MN-32</taxon>. Mutations in the human gene leads to a fatal neurodegenerative disease [<cite idref="PUB00011905"/>]. </p>