<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>Metalloproteases are the most diverse of the four main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site [<cite idref="PUB00003579"/>]. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [<cite idref="PUB00003579"/>].</p><p>This entry contains thyrotropin-releasing hormone degrading ectoenzyme (TRH-DE), which is a metallopeptidase belonging to MEROPS peptidase family M1 (clan MA(E)); it is alternatively known as pyroglutamyl-peptidase II (PPII).</p><p>The M1 family of zinc metallopeptidases is widely distributed in nature, with homologues found in bacteria, fungi, plants, invertebrates, amphibians, birds, and mammals. They have a critical role in many physiological processes that involve or are dependent on the maturation, activation, and degradation of peptides. All members of the M1 family are aminopeptidases, except for TRH-DE, which is a membrane-bound omegapeptidase that catalyzes the inactivation of the neuropeptide thyrotropin-releasing hormone (TRH) in the extracellular space [<cite idref="PUB00034927"/>]. TRH is a neurohormone that regulates adenohypophysial secretions and a neurotransmitter with effects on multiple central nervous system functions, including cognition and locomotion [<cite idref="PUB00035557"/>]. </p><p>TRH-DE is a 1,024-amino acid type II integral transmembrane protein has 12 putative C-terminal N-glycosylation sites, a potential tyrosine sulphation site (residue 380), a consensus sequence for zinc-dependent metallopeptidases, and a short N-terminal intracellular domain with a potential phosphorylation site [<cite idref="PUB00034927"/>].</p> Peptidase M1, thyrotropin-releasing hormone degrading ectoenzyme