Family M16
Summary for family M16
| Name | Peptidase family M16 (pitrilysin family) |
|---|
| Family type peptidase | M16.001 - pitrilysin (Escherichia coli), MEROPS Accession MER0001222 (peptidase unit: 24-232) |
| Content of family | Peptidase family M16 contains metalloendopeptidases. |
| History |
Identifier created: Biochem.J. 290:205-218 (1993)
Pitrilysin has been reviewed by Roth, 2004, and chapters on seven other peptidases in family M16 are to be found in the same volume. |
| Catalytic type | Metallo |
| Active site | Two of the zinc ligands occur in the motif His-Xaa-Xaa-Glu-His, almost the reverse of the HEXXH motif found in clan MA. The glutamate in this HXXEH motif is important for catalysis, and a glutamate more C-terminal is the third zinc ligand (Becker & Roth, 1992; Taylor et al., 2001). Mutation of glutamate-162 mutant produced a protein that retained 20% of the activity of the wild-type enzyme (Becker & Roth, 1993). |
| Activities and specificities | The specificities of peptidases in family M16 are varied, but the site of cleavage is seldom far from a terminus of the substrate molecule. A possible explanation for this is suggested by the structure of mitochondrial processing peptidase (MPP) (see below) in which the active site is sterically hindered; this may be general in the family. Good assays can be made with oligopeptides that are derivatised as quenched-fluoresence substrates (Anastasi et al., 1993; Song et al., 2001). The specificity of pitrilysin (M16.001) was described by Anastasi et al., 1993. The sites of cleavage by peptidases in the family (see the respective Substrates data pages) often include bonds on the amino side of arginine, and nardilysin (M16.005) has a definite preference for cleavage of Xaa Arg bonds (Chow et al., 2003). MMP cleaves N-terminal, mitochondrial targeting signals from proteins as they are imported to the mitochondrion. These signal peptides tend to contain basic amino acid residues, and it has been noted that the wall of the active site cavity contains acidic side chains that could explain this specificity (Kitada & Ito, 2001).
Insulysin is activated by thiol compounds (Perlman et al., 1993) which is an unusual characteristic for a metallopeptidase not seen with other members of the family. |
| Inhibitors | Like other metallopeptidases, those in family M16 are inhibited by chelating agents. Some of the peptidases are weakly and non-specifically inhibited by bacitracin, or a bacitracin-zinc complex (e.g. Anastasi et al., 1993). Few potent or specific inhibitors for peptidases in the family have been described. |
| Molecular structure | Structural data are available for MPP, the molecule of which is a heterodimer composed of the catalytically-active beta-subunit (M16.003) and the homologous, but non-peptidase, alpha-subunit (M16.971). The active site of M16.003, structurally similar to that of thermolysin despite the reversal of the motif, is located within a large cavity between the subunits. A glycine-rich region that forms an insert in the alpha-subunit restricts access to the central cavity. |
| Clan | ME |
| Basis of clan assignment | Type family of clan ME. |
| Biological functions | MPP removes an N-terminal targeting signal from mitochondrial protein molecules that have been synthesized in the cytoplasm as they are imported into the mitochondrion. There is much interest in the possibility that insulysin (M16.002) may be a physiologically significant alpha-secretase, usefully degrading the amyloidogenic Alzheimer"s beta-peptide (Edland, 2004). |
| Statistics for family M16 | Sequences: | 27911 |
| Identifiers: | 58 |
| Identifiers with PDB entries: | 20 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| mitochondrial processing peptidase beta-subunit | M16.003 | Yes |
| chloroplast (stromal) processing peptidase | M16.004 | - |
| hydrogenosomal processing peptidase | M16.015 | - |
| YMXG peptidase | M16.016 | - |
| YMXG peptidase | M16.019 | Yes |
| SPH2682 protein (Sphingomonas sp. strain A1) | M16.970 | Yes |
| mitochondrial processing peptidase non-peptidase alpha subunit | M16.971 | - |
| ubiquinol-cytochrome c reductase core protein I | M16.973 | Yes |
| ubiquinol-cytochrome c reductase core protein II | M16.974 | Yes |
| Mername-AA224 non-peptidase homologue | M16.975 | - |
| mitochondrial processing peptidase beta-like protein | M16.977 | - |
| protein similar to mitochondrial processing peptidase beta (Rattus norvegicus) | M16.978 | - |
| mitochondrial processing peptidase beta subunit domain 2 | M16.980 | - |
| ubiquinol-cytochrome c reductase core protein domain 2 | M16.981 | Yes |
| mitochondrial processing peptidase subunit alpha unit 2 | M16.985 | - |
| Fjoh_2253 protein (Flavobacterium johnsoniae) | M16.986 | Yes |
| At5g56730 (Arabidopsis thaliana)-like peptidase | M16.A03 | - |
| PqqL protein (Escherichi coli) | M16.A05 | - |
| BSSC8_26020 g.p. (Bacillus subtilis) | M16.A15 | Yes |
| albF g.p. (Bacillus subtilis) | M16.A16 | - |
| ymfH g.p. (Bacillus subtilis) | M16.A20 | Yes |
| PF14_0382 g.p. (Plasmodium falciparum) | M16.A21 | - |
| LOC133083 g.p. (Homo sapiens) | M16.P01 | - |
| Subfamily M16B non-peptidase homologues | non-peptidase homologue | Yes |
| Subfamily M16B unassigned peptidases | unassigned | Yes |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| eupitrilysin | M16.009 | Yes |
| falcilysin | M16.011 | Yes |
| PreP1 peptidase (Arabidopsis-type) | M16.012 | Yes |
| CYM1 peptidase (Saccharomyces cerevisiae) | M16.013 | - |
| PreP2 peptidase (Arabidopsis-type) | M16.018 | - |
| insulysin homologue (Saccharomyces cerevisiae) | M16.A04 | - |
| C05D11.1 g.p. (Caenorhabditis elegans) | M16.A12 | - |
| DDB_G0287909 g.p. (Dictyostelium discoideum) | M16.A17 | - |
| DDB_G0290415 g.p. (Dictyostelium discoideum) | M16.A18 | - |
| cym1 g.p. (Schizosaccharomyces pombe) | M16.A19 | - |
| PF11_0189 g.p. (Plasmodium falciparum) | M16.A22 | - |
| Subfamily M16C non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M16C unassigned peptidases | unassigned | - |
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Peptidases not assigned to subfamily
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