InterPro: IPR000126 Peptidase S1B, active site

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:

• 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-, 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.
• Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; 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 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.

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [1]. 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 [1]. 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 [1].

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 [1]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds [1]. 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) [1, 2].

In a number of prokaryotic proteases the catalytic activity is provided by a charge relay system analogous to that of the trypsin family of serine proteases, but which probably evolved by independent convergent evolution [3, 4]. The sequences around the catalytic residues (Asp, Ser and His) are completely different from those of the corresponding residues in trypsin serine proteases, although these proteins also contain the serine protease trypsin family signatures. These two signatures cover the Ser and His active sites.

Sequences with these active site signatures belong to MEROPS subfamily S1B (clan PA(S)); the type example being glutamyl endopeptidase I of Staphylococcus aureus [1]. Other peptidases with these active site signatures include S. aureus V8 protease, which preferentially cleaves peptide bonds C-terminal to Asp and Glu residues; Bacillus licheniformis glutamate-specific endopeptidase [5], which also cleaves on the C-terminal side of acidic residues, but with strong preference for glutamate; Bacillus subtilis extracellular 'metalloprotease' [6]; and S. aureus exfoliative (or epidermolytic) toxins A and B, which cause impetigous diseases (also known as Staphylococcal scalded skin syndrome).