{PDOC52034}
{PS52034; PEPTIDASE_M32}
{BEGIN}
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* Peptidase family M32 domain profile *
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Carboxypeptidases (CPs)  are  a  group of hydrolases that perform many diverse
physiological functions  by  removing C-terminal amino acids from proteins and
peptides. According  to  the  chemical  nature  of their catalytic site, these
hydrolases can   be   divided   into   three   major  classes,  namely  serine
carboxypeptidases, cysteine  carboxypeptidases,  and  metallocarboxypeptidases
(MCPs), with  the latter group usually employing zinc as a catalytic cofactor.
Among MCPs,  the  M32  or  Thermus  aquaticus  carboxypeptidase (TaqCP) family
consists of  a  large  number  of enzymes with broad specificity. This family,
which possesses   the   classical   HEXXH  motif  observed  in  numerous  zinc
metalloproteases, is  broadly  distributed among prokaryotic organisms, but so
far it  has  been  found only in a few eukaryotes, namely some green algae and
trypanosomatids [1,2,3].

The M32  family metallocarboxypeptidase domain is mostly helical, except for a
three-stranded beta  sheet  near  the  active site (see <PDB:1K9X>. There is a
deep substrate-binding  groove  that  traverses the length of the domain. When
viewed along  the  substrate  groove,  the  protein  can  be  divided into two
subdomains associated   with   the   substrate   binding   and   dimerization,
respectively. The  active  site  lies at the bottom of the groove and contains
the canonical HEXXH motif that includes the active-site glutamic acid residue,
flanked by two histidine residues that coordinate the catalytic metal ion. The
third metal  ligand  glutamic  acid  residue  is  found  in  the HE[GS]Q motif
conserved in  all  M32  family  metallocarboxypeptidases. It has been proposed
that the metal serves to stabilize a bound water/hydroxide and/or activate the
scissile carbonyl of the substrate by serving as a Lewis acid. The active site
glutamate of  the  HEXXH  motif  assists  in  the  nucleophilic  attack of the
activated water/hydroxide   on   the   carbonyl   to   form   the  tetrahedral
intermediate, by  acting  as a general acid/base that can shuttle the hydrogen
atom from the activated water to the scissile amide nitrogen of the substrate.
Protonation of  this  amide  nitrogen makes it a better leaving group, thereby
facilitating cleavage of the amide bond [4,5].

The profile we developed covers the entire peptidase family M32 domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: August 2023 / First entry.

[ 1] Niemirowicz G., Parussini F., Agueero F., Cazzulo J.J.
     "Two metallocarboxypeptidases from the protozoan Trypanosoma cruzi
     belong to the  M32 family, found so far only in prokaryotes."
     Biochem. J. 401:399-410(2007).
     PubMed=17007610; DOI=10.1042/BJ20060973
[ 2] Frasch A.P., Carmona A.K., Juliano L., Cazzulo J.J., Niemirowicz G.T.
     "Characterization of the M32 metallocarboxypeptidase of Trypanosoma
     brucei:  differences and similarities with its orthologue in
     Trypanosoma cruzi."
     Mol. Biochem. Parasitol. 184:63-70(2012).
     PubMed=22575602; DOI=10.1016/j.molbiopara.2012.04.008
[ 3] Frasch A.P., Bouvier L.A., Oppenheimer F.M., Juliano M.A., Juliano L.,
     Carmona A.K., Cazzulo J.J., Niemirowicz G.T.
     "Substrate specificity profiling of M32 metallocarboxypeptidases from
     Trypanosoma  cruzi and Trypanosoma brucei."
     Mol. Biochem. Parasitol. 219:10-16(2018).
     PubMed=29246805; DOI=10.1016/j.molbiopara.2017.12.001
[ 4] Arndt J.W., Hao B., Ramakrishnan V., Cheng T., Chan S.I., Chan M.K.
     "Crystal structure of a novel carboxypeptidase from the
     hyperthermophilic archaeon  Pyrococcus furiosus."
     Structure 10:215-224(2002).
     PubMed=11839307; DOI=10.1016/s0969-2126(02)00698-6
[ 5] Lee Y.-J., Dhanasingh I., Ahn J.-S., Jin H.-S., Choi J.M., Lee S.H.,
     Lee D.-W.
     "Biochemical and structural characterization of a keratin-degrading
     M32  carboxypeptidase from Fervidobacterium islandicum AW-1."
     Biochem. Biophys. Res. Commun. 468:927-933(2015).
     PubMed=26603937; DOI=10.1016/j.bbrc.2015.11.058

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