Family M14

Family

Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

M14A

Summary Holotypes Alignment Tree Genomes Literature

M14B

Summary Holotypes Alignment Tree Genomes Literature

M14C

Summary Holotypes Alignment Tree Genomes Literature

M14D

Summary Holotypes Alignment Tree Genomes Literature

Summary for family M14

NamePeptidase family M14 (carboxypeptidase A family)
Family type peptidaseM14.001 - carboxypeptidase A1 (Homo sapiens), MEROPS Accession MER0001190 (peptidase unit: 111-419)
Content of familyPeptidase family M14 contains metallocarboxypeptidases.
History Identifier created: Biochem.J. 290:205-218 (1993)
Pancreatic carboxypeptidase A (M14.001) was discovered in about 1929 (Waldschmidt-Leitz & Purr, 1929) and crystallised in 1935 (Anson, 1935).
Catalytic typeMetallo
Active siteThe single catalytic zinc ion is tetrahedrally coordinated by two histidines and a glutamate, as well as a water molecule. One of the histidines and the glutamate occur in the motif His-Xaa-Xaa-Glu, and the third zinc ligand is 103143 residues C-terminal to this motif (see the Alignment). The catalytic mechanism of carboxypeptidase A and its homologues has been reviewed by Auld, 2004.
The mechanism of regulation of activity of the procarboxypeptidases by their propeptides has been discussed in conjunction with the structures (e.g. Guasch et al., 1992).
Activities and specificitiesMost of the peptidases in the family are carboxypeptidases, hydrolysing single, C-terminal amino acids from polypeptide chains. They have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Two main types of specificity are illustrated by carboxypeptidase A (M14.001), which favours residues with aromatic or branched side chains, and carboxypeptidase B (M14.003), which prefers basic amino acids. An exceptional type of activity in the family (in subfamily C) is the dipeptidyl-peptidase activity of gamma-glutamyl-(L)-meso-diaminopimelate peptidase I (M14.008) from Bacillus sphaericus, involved in bacterial cell wall metabolism.
InhibitorsNumerous chemical inhibitors of the carboxypeptidases in family M14 have been described. Examples are 2-benzyl-3,4-iminobutanoic acid for carboxypeptidase A (Park & Kim, 2001), and guanidinoethylmercaptosuccinic acid for the enzymes with carboxypeptidase B-like specificity (Aloy et al., 2001). Protein inhibitors are the potato carboxypeptidase inhibitor (I37.001) and leech carboxypeptidase A inhibitor (I46.001).
Molecular structureTertiary structures solved for several members of the family show a fold containing an alpha/beta/alpha sandwich structure with an antiparallel beta-sheet of eight strands. The fold shows some similarity to those of metallopeptidases in which two zinc atoms are essential for activity in families M17 and M28. The similarity is especially marked in the central beta sheet, but the relative positions of the zinc ligands are not conserved between the families, and family M14 is placed in its own clan MC.
Metallocarboxypeptidase D is unusual in containing three peptidase units, only the first two of which (M14.011, M14.016) can be active because the zinc ligand Glu72 is replaced by Ala in the third domain (M14.950).
ClanMC
Basis of clan assignmentType family of clan MC.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsThe enzymes are synthesised without signal peptides, but there are commonly propepides that must be processed to give the active enzymes. The mature enzymes are generally soluble (e.g. carboxypeptidase A, carboxypeptidase B, carboxypeptidase U (M14.009)), but carboxypeptidase M (M14.006) is membrane-bound through a glycosylphosphatidylinositol anchor. The functions of the enzymes are numerous and diverse (see Literature for the individual enzymes). They include digestion of food (pancreatic carboxypeptidases A and B), processing of bioactive peptides (carboxypeptidase E, M14.005), and the metabolism of bacterial cell walls (gamma-glutamyl-(L)-meso-diaminopimelate peptidase I).
Pharmaceutical and biotech relevanceCarboxypeptidase U (M14.009) is of particular interest as a potential drug target because of its role in blood coagulation (Hendriks, 2004). The enzyme is activated by thrombin and once activated, potently attenuates fibrinolysis.
Statistics for family M14Sequences:12466
Identifiers:74
Identifiers with PDB entries:12
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily M14A
Name Peptidase subfamily M14A
Subfamily type peptidase M14.001 - carboxypeptidase A1 (Homo sapiens), MEROPS Accession MER0001190 (peptidase unit: 111-419)
Active site residues H179 E182 R237 H306 E380 
Statistics Sequences: 6176
Identifiers: 40
Identifiers with PDB entries: 8
Other databases CATH 3.40.630.10
HOMSTRAD cpa
HSSP 8cpa
INTERPRO IPR003146
PANTHER PTHR11705
PFAM PF00246
SCOP 53188
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
carboxypeptidase A1M14.001Yes
carboxypeptidase A2M14.002Yes
carboxypeptidase BM14.003Yes
carboxypeptidase TM14.007Yes
carboxypeptidase B2M14.009Yes
carboxypeptidase A3M14.010-
carboxypeptidase MeCPAM14.014-
carboxypeptidase A4M14.017Yes
carboxypeptidase A6M14.018-
carboxypeptidase A5M14.020-
metallocarboxypeptidase OM14.021-
insect gut carboxypeptidase-1M14.024Yes
insect gut carboxypeptidase-2M14.031-
insect gut carboxypeptidase-3M14.032Yes
suro-1 carboxypeptidaseM14.035-
CG32379 protein (Drosophila melanogaster)M14.A03-
CG8560 protein (Drosophila melanogaster)M14.A04-
CG2915 protein (Drosophila melanogaster)M14.A05-
CG12374 protein (Drosophila melanogaster)M14.A06-
CG4408 protein (Drosophila melanogaster)M14.A07-
CG17633 protein (Drosophila melanogaster)M14.A08-
CG4017 protein (Drosophila melanogaster)M14.A09-
CG7025 protein (Drosophila melanogaster)M14.A10-
CG18585 protein (Drosophila melanogaster)M14.A11-
CG14820 protein (Drosophila melanogaster)M14.A12-
CG8564 protein (Drosophila melanogaster)M14.A13-
CG8563 protein (Drosophila melanogaster)M14.A14-
CG8562 protein (Drosophila melanogaster)M14.A15-
CG18417 protein (Drosophila melanogaster)M14.A16-
CG8539 protein (Drosophila melanogaster)M14.A17-
CG3108 protein (Drosophila melanogaster)M14.A18-
CG3097 protein (Drosophila melanogaster)M14.A19-
T06A4.1 g.p. (Caenorhabditis elegans)M14.A22-
Y47G6A.19 g.p. (Caenorhabditis elegans)M14.A23-
T06A4.3 g.p. (Caenorhabditis elegans)M14.A24-
Y59C2A.1 g.p. (Caenorhabditis elegans)M14.A25-
F02D8.4 g.p. (Caenorhabditis elegans)M14.A26-
W01A8.6 g.p. (Caenorhabditis elegans)M14.A27-
Y18H1A.9 g.p. (Caenorhabditis elegans)M14.A28-
ZC434.9 g.p. (Caenorhabditis elegans)M14.A34-
subfamily M14A non-peptidase homologuesnon-peptidase homologue-
subfamily M14A unassigned peptidasesunassigned-
Subfamily M14B
Name Peptidase subfamily M14B
Subfamily type peptidase M14.005 - carboxypeptidase E (Bos taurus), MEROPS Accession MER0001202 (peptidase unit: 42-475)
Active site residues H113 E116 R178 H247 E341 
Statistics Sequences: 5826
Identifiers: 28
Identifiers with PDB entries: 3
Other databases CATH 8.1.24.1
HOMSTRAD hs1qmua
INTERPRO IPR003146
PANTHER PTHR11532
PFAM PF00246
SCOP 53188
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
carboxypeptidase NM14.004Yes
carboxypeptidase EM14.005-
carboxypeptidase MM14.006Yes
metallocarboxypeptidase D peptidase unit 1M14.011Yes
metallocarboxypeptidase ZM14.012-
metallocarboxypeptidase D peptidase unit 2M14.016-
CPG70 carboxypeptidase (Porphyromonas gingivalis)M14.023-
cytosolic carboxypeptidase-like protein 5M14.025-
cytosolic carboxypeptidase 3M14.026-
cytosolic carboxypeptidase 1M14.028-
cytosolic carboxypeptidase 2M14.029-
cytosolic carboxypeptidase 4M14.030-
EGL-21 peptidaseM14.033-
murein peptide amidase MpaAM14.034-
protein Silver domain 1M14.037-
metallocarboxypeptidase D non-peptidase unitM14.950-
adipocyte-enhancer binding protein 1M14.951-
carboxypeptidase-like protein X1;CPX-1 g.p. (Mus musculus)M14.952-
carboxypeptidase-like protein X2M14.953-
CPX2 proteinM14.954-
M14.955-
At5g42320 (Arabidopsis thaliana)M14.A01-
At1g71696 (Arabidopsis thaliana)M14.A02-
silver protein domain 2 (Drosophila melanogaster)M14.A20-
F59A3.1 g.p. (Caenorhabditis elegans)M14.A29-
T27A8.1 g.p. (Caenorhabditis elegans)M14.A30-
DDB_G0288963 g.p. (Dictyostelium discoideum)M14.A33-
PFA0170c g.p. (Plasmodium falciparum)M14.A35-
subfamily M14B non-peptidase homologuesnon-peptidase homologue-
subfamily M14B unassigned peptidasesunassigned-
Subfamily M14C
Name Peptidase subfamily M14C
Subfamily type peptidase M14.008 - gamma-D-glutamyl-(L)-meso-diaminopimelate peptidase I (Lysinibacillus sphaericus), MEROPS Accession MER0001505 (peptidase unit: 103-398)
Active site residues H164 E167 H309 E368 
Statistics Sequences: 171
Identifiers: 1
Identifiers with PDB entries: 0
Other databases INTERPRO IPR002482
PANTHER PTHR11705
PFAM PF00246
PFAM PF01476
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
gamma-D-glutamyl-(L)-meso-diaminopimelate peptidase IM14.008-
hypothetical protein YcjI (Escherichia coli)non-peptidase homologue-
subfamily M14C unassigned peptidasesunassigned-
Subfamily M14D
Name Peptidase subfamily M14D
Subfamily type peptidase M14.027 - cytosolic carboxypeptidase 6 (Homo sapiens), MEROPS Accession MER0033178 (peptidase unit: 8-148)
Active site residues H45 E48 E,R95 H143 
Statistics Sequences: 133
Identifiers: 4
Identifiers with PDB entries: 0
Other databases PANTHER PTHR12756
PFAM PF00246
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
cytosolic carboxypeptidase 6M14.027-
CG11428 (Drosophila melanogaster)M14.A21-
ccpp-6 g.p. (Caenorhabditis elegans)M14.A31-
Cg31019-pa (Drosophila melanogaster)M14.A32-
subfamily M14D non-peptidase homologuesnon-peptidase homologue-
subfamily M14D unassigned peptidasesunassigned-
Peptidases not assigned to subfamily
Peptidases and Homologues MEROPS ID Structure
PGP1 D,L-carboxypeptidase (Campylobacter jejuni)M14.038-
family M14 non-peptidase homologuesnon-peptidase homologue-
family M14 unassigned peptidasesunassignedYes