Family M15

Family

Summary Holotypes Alignment Tree Genomes Structure Literature

M15A

Summary Holotypes Alignment Tree Genomes Literature

M15B

Summary Holotypes Alignment Tree Genomes Literature

M15C

Summary Holotypes Alignment Tree Genomes Literature

M15D

Summary Holotypes Alignment Tree Genomes Literature

Summary for family M15

Family type peptidaseM15.001 - zinc D-Ala-D-Ala carboxypeptidase (Streptomyces-type) (Streptomyces albus), MEROPS Accession MER0001357 (peptidase unit: 116-255)
Content of familyPeptidase 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 typeMetallo
Active siteActive 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 specificitiesA detailed study of the specificity of Streptomyces zinc D-Ala-D-Ala carboxypeptidase with substrates of the type Xaa-YaaZaa (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).
InhibitorsInhibitors 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 structureThe 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.
ClanMD
Basis of clan assignmentType family of clan MD.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsThe 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 relevanceThe 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 M15Sequences:5883
Identifiers:13
Identifiers with PDB entries:6
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily M15A
Name Peptidase subfamily M15A
Subfamily type peptidase M15.001 - zinc D-Ala-D-Ala carboxypeptidase ({Streptomyces}-type) (Streptomyces albus), MEROPS Accession MER0001357 (peptidase unit: 116-255)
Active site residues H196 D203 H237 H239 
Statistics Sequences: 503
Identifiers: 1
Identifiers with PDB entries: 1
Other databases CATH 3.30.1380.10
HOMSTRAD hsd1lbu_2
HSSP 1lbu
INTERPRO IPR002477
INTERPRO IPR010275
PFAM PF01471
PFAM PF05951
PFAM PF08291
SCOP 55167
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)M15.001Yes
subfamily M15A non-peptidase homologuesnon-peptidase homologue-
subfamily M15A unassigned peptidasesunassigned-
Subfamily M15B
Name Peptidase subfamily M15B
Subfamily type peptidase M15.010 - vanY D-Ala-D-Ala carboxypeptidase (Enterococcus faecium), MEROPS Accession MER0001333 (peptidase unit: 22-303)
Active site residues H163 D170 E213 H216 
Statistics Sequences: 2771
Identifiers: 4
Identifiers with PDB entries: 1
Other databases INTERPRO IPR003709
PFAM PF02557
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
DD-carboxypeptidase pdcA (Myxococcus-type)M15.002-
van XYc peptidaseM15.003-
vanY D-Ala-D-Ala carboxypeptidaseM15.010-
DacB metallopeptidase (Streptococcus pneumoniae)M15.024Yes
subfamily M15B non-peptidase homologuesnon-peptidase homologue-
subfamily M15B unassigned peptidasesunassigned-
Subfamily M15C
Name Peptidase subfamily M15C
Subfamily type peptidase M15.020 - Ply118 L-Ala-D-Glu peptidase (bacteriophage A118), MEROPS Accession MER0004957 (peptidase unit: 1-281)
Active site residues H66 D73 D115 H118 
Statistics Sequences: 980
Identifiers: 6
Identifiers with PDB entries: 3
Other databases INTERPRO IPR003709
PFAM PF01510
PFAM PF02557
PFAM PF13539
SCOP 160436
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
Ply118 L-Ala-D-Glu peptidaseM15.020-
Ply500 L-Ala-D-Glu peptidaseM15.021Yes
L-alanyl-D-glutamate peptidase (bacteriophage T5)M15.022Yes
lysin LysA2 (Lactobacillus casei bacteriophage A2) and similarM15.023Yes
Ply511 amidaseM15.950-
ycdD g.p. (Bacillus subtilis)M15.A05-
subfamily M15C non-peptidase homologuesnon-peptidase homologue-
subfamily M15C unassigned peptidasesunassigned-
Subfamily M15D
Name Peptidase subfamily M15D
Subfamily type peptidase M15.011 - vanX D-Ala-D-Ala dipeptidase (Enterococcus faecium), MEROPS Accession MER0001602 (peptidase unit: 50-189)
Active site residues H116 D123 E181 D,H184 
Statistics Sequences: 1629
Identifiers: 2
Identifiers with PDB entries: 1
Other databases CATH 3.30.1380.10
HOMSTRAD hs1o86a
INTERPRO IPR000755
PANTHER PTHR22935
PFAM PF01427
SCOP 111022
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
vanX D-Ala-D-Ala dipeptidaseM15.011Yes
Aad peptidaseM15.012-
subfamily M15D non-peptidase homologuesnon-peptidase homologue-
subfamily M15D unassigned peptidasesunassigned-
Peptidases not assigned to subfamily
Peptidases and Homologues MEROPS ID Structure
family M15 non-peptidase homologuesnon-peptidase homologue-
family M15 unassigned peptidasesunassigned-