PROSITE documentation PDOC52034Peptidase family M32 domain profile
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 β 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.
Last update:August 2023 / First entry.
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PROSITE method (with tools and information) covered by this documentation:
| 1 | Authors | Niemirowicz G. Parussini F. Agueero F. Cazzulo J.J. |
| Title | Two metallocarboxypeptidases from the protozoan Trypanosoma cruzi belong to the M32 family, found so far only in prokaryotes. | |
| Source | Biochem. J. 401:399-410(2007). | |
| PubMed ID | 17007610 | |
| DOI | 10.1042/BJ20060973 |
| 2 | Authors | Frasch A.P. Carmona A.K. Juliano L. Cazzulo J.J. Niemirowicz G.T. |
| Title | Characterization of the M32 metallocarboxypeptidase of Trypanosoma brucei: differences and similarities with its orthologue in Trypanosoma cruzi. | |
| Source | Mol. Biochem. Parasitol. 184:63-70(2012). | |
| PubMed ID | 22575602 | |
| DOI | 10.1016/j.molbiopara.2012.04.008 |
| 3 | Authors | Frasch A.P. Bouvier L.A. Oppenheimer F.M. Juliano M.A. Juliano L. Carmona A.K. Cazzulo J.J. Niemirowicz G.T. |
| Title | Substrate specificity profiling of M32 metallocarboxypeptidases from Trypanosoma cruzi and Trypanosoma brucei. | |
| Source | Mol. Biochem. Parasitol. 219:10-16(2018). | |
| PubMed ID | 29246805 | |
| DOI | 10.1016/j.molbiopara.2017.12.001 |
| 4 | Authors | Arndt J.W. Hao B. Ramakrishnan V. Cheng T. Chan S.I. Chan M.K. |
| Title | Crystal structure of a novel carboxypeptidase from the hyperthermophilic archaeon Pyrococcus furiosus. | |
| Source | Structure 10:215-224(2002). | |
| PubMed ID | 11839307 | |
| DOI | 10.1016/s0969-2126(02)00698-6 |
| 5 | Authors | Lee Y.-J. Dhanasingh I. Ahn J.-S. Jin H.-S. Choi J.M. Lee S.H. |
| Title | Lee D.-W. Biochemical and structural characterization of a keratin-degrading M32 carboxypeptidase from Fervidobacterium islandicum AW-1. | |
| Source | Biochem. Biophys. Res. Commun. 468:927-933(2015). | |
| PubMed ID | 26603937 | |
| DOI | 10.1016/j.bbrc.2015.11.058 |
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