Family M15
Summary for family M15
| Family type peptidase | M15.001 - zinc D-Ala-D-Ala carboxypeptidase (Streptomyces-type) (Streptomyces albus), MEROPS Accession MER0001357 (peptidase unit: 116-255) |
| Content of family | Peptidase family M15 contains metallopeptidases, mostly specialised carboxypeptidases and dipeptidases. |
| History |
Identifier created: Biochem.J. 290:205-218 (1993)
Several of the peptidases in family M15 have been reviewed: Streptomyces zinc D-Ala-D-Ala carboxypeptidase (M15.001) by Ghuysen (2004), VanY D-Ala-D-Ala carboxypeptidase (M15.010) by Wright, 2004 and VanX D-Ala-D-Ala carboxypeptidase (M15.011) by Lessard, 2004. |
| Catalytic type | Metallo |
| Active site | Active site residues in zinc D-Ala-D-Ala carboxypeptidase (M15.001) are His154, Asp161 and His197 (see the Alignment). The zinc ligands are revealed by the crystal structure (see Structure for M15.001). Mutagenesis was used by McCafferty et al. (1997) to identify the catalytic residues of vanX D-Ala-D-Ala dipeptidase. Residues forming the specificity sites in the VanX peptidase were identified by Lessard & Walsh (1999). |
| Activities and specificities | A detailed study of the specificity of Streptomyces zinc D-Ala-D-Ala carboxypeptidase with substrates of the type Xaa-Yaa Zaa (Leyh-Bouille et al., 1970) showed that the peptidase required the amino terminus of the substrate to be blocked and the C-terminus to be free. Both Yaa and Zaa should be in the D-configuration, preferably Ala. Chromogenic assays are available for the evaluation of inhibitors of the VanX dipeptidase (Anissimova et al., 2003). The bacteriophage endolysins PLY118 and PLY500 (M15.020) cleave between L-Ala and D-Glu residues of Listeria cell wall peptidoglycan (Loessner et al., 1995). |
| Inhibitors | Inhibitors of Streptomyces zinc D-Ala-D-Ala carboxypeptidase with thiol, hydroxamate or carboxylate metal-binding functions were described by Charlier et al., 1984. Inhibitors of the VanX dipeptidase have been reviewed by Gao, 2002. |
| Molecular structure | The 1.8 Angstrom structure of zinc D-Ala-D-Ala carboxypeptidase (Ghuysen, 2004) shows an alpha/beta-protein with mainly antiparallel beta-sheets. There is a non-catalytic N-terminal module that carries a substrate-recognition and -binding site (Ghuysen, 1994). The structure of the VanX dipeptidase (Bussiere et al., 1998) was reported together with those of complexes with a substrate and with phosphonate and phosphinate transition-state analogue inhibitors. The fold of VanX was similar to those of the Streptomyces zinc D-Ala-D-Ala carboxypeptidase and the non-peptidase N-terminal domain of the mouse Sonic hedgehog protein.
It has been suggested that an evolutionary relationship exists between the metallopeptidases of family M15 (in clan MD) and those of family M23 containing lysostaphin in clan MO (Bochtler et al., 2004). It is proposed that similar active sites contain Zn2+ tetrahedrally coordinated by two histidines, an aspartate, and a water molecule with the same core folding motif although in otherwise highly divergent protein folds. |
| Clan | MD |
| Basis of clan assignment | Type family of clan MD. |
| Biological functions | The peptidases of family M15 are involved in bacterial cell wall biosynthesis and metabolism. They include zinc-dependent D-Ala-D-Ala carboxypeptidases and dipeptidases, and bacteriophage endolysins. The structure of the peptidoglycan polymer that constitutes the Streptomyces cell wall is stabilised by a cross-linking peptide that contains D-amino acids. The cross-linking peptide is synthesized as a precursor with an additional C-terminal D-Ala residue. The removal of the C-terminal D-Ala by the carboxypeptidase prepares the precursor for incorporation into the cell wall (a transpeptidation reaction catalysed by a serine-type D-Ala-D-Ala transpeptidase, S11.004). Vancomycin-resistant enterococci are pathogenic bacteria that attenuate antibiotic sensitivity by producing peptidoglycan precursors that terminate in D-Ala-D-lactate rather than D-Ala-D-Ala. A key enzyme in antibiotic resistance is the metallodipeptidase VanX that reduces the cellular pool of the D-Ala-D-Ala dipeptide so that only the resistant D-Ala-D-lactate is incorporated into the cell wall (Lessard & Walsh, 1999). |
| Pharmaceutical and biotech relevance | The VanX and VanY D-Ala-D-Ala peptidases confer resistance to the antibiotic vancomycin on some strains of enterococci, and are therefore drug targets. The substrate specificities of VanX and VanY ensure that essentially only precursors with low affinity for the glycopeptide antibiotics are available for peptidoglycan synthesis in resistant strains (Reynolds, 1998). |
| Statistics for family M15 | Sequences: | 10572 |
| Identifiers: | 13 |
| Identifiers with PDB entries: | 8 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| zinc D-Ala-D-Ala carboxypeptidase (Streptomyces-type) | M15.001 | Yes |
| Subfamily M15A non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M15A unassigned peptidases | unassigned | - |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| DD-carboxypeptidase pdcA (Myxococcus-type) | M15.002 | - |
| van XYc peptidase | M15.003 | Yes |
| vanY D-Ala-D-Ala carboxypeptidase | M15.010 | - |
| DacB metallopeptidase (Streptococcus pneumoniae) | M15.024 | Yes |
| Subfamily M15B non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M15B unassigned peptidases | unassigned | Yes |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| Ply118 L-Ala-D-Glu peptidase | M15.020 | - |
| Ply500 L-Ala-D-Glu peptidase | M15.021 | Yes |
| L-alanyl-D-glutamate peptidase (bacteriophage T5) | M15.022 | Yes |
| lysin LysA2 (Lactobacillus casei bacteriophage A2) and similar | M15.023 | - |
| Ply511 amidase | M15.950 | - |
| ycdD g.p. (Bacillus subtilis) | M15.A05 | - |
| Subfamily M15C non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M15C unassigned peptidases | unassigned | Yes |
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Peptidases not assigned to subfamily
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