Family M14
Summary for family M14
| Name | Peptidase family M14 (carboxypeptidase A family) |
|---|
| Family type peptidase | M14.001 - carboxypeptidase A1 (Homo sapiens), MEROPS Accession MER0001190 (peptidase unit: 111-419) |
| Content of family | Peptidase 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 type | Metallo |
| Active site | The 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 103–143 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 specificities | Most 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. |
| Inhibitors | Numerous 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 structure | Tertiary 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). |
| Clan | MC |
| Basis of clan assignment | Type family of clan MC. |
| Biological functions | The 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 relevance | Carboxypeptidase 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 M14 | Sequences: | 19935 |
| Identifiers: | 76 |
| Identifiers with PDB entries: | 17 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| carboxypeptidase A1 | M14.001 | Yes |
| carboxypeptidase A2 | M14.002 | Yes |
| carboxypeptidase B | M14.003 | Yes |
| carboxypeptidase T | M14.007 | Yes |
| carboxypeptidase B2 | M14.009 | Yes |
| carboxypeptidase A3 | M14.010 | - |
| carboxypeptidase MeCPA | M14.014 | - |
| carboxypeptidase A4 | M14.017 | Yes |
| carboxypeptidase A6 | M14.018 | - |
| carboxypeptidase A5 | M14.020 | - |
| metallocarboxypeptidase O | M14.021 | Yes |
| insect gut carboxypeptidase-1 | M14.024 | Yes |
| suro-1 carboxypeptidase | M14.035 | - |
| CG32379 g.p. (Drosophila melanogaster) | M14.A03 | - |
| CG8560 protein (Drosophila melanogaster) | M14.A04 | - |
| CG2915 g.p. (Drosophila melanogaster) | M14.A05 | - |
| CG12374 g.p. (Drosophila melanogaster) | M14.A06 | - |
| CG4408 g.p. (Drosophila melanogaster) | M14.A07 | - |
| CG17633 g.p. (Drosophila melanogaster) | M14.A08 | - |
| CG4017 g.p. (Drosophila melanogaster) | M14.A09 | - |
| CG7025 g.p. (Drosophila melanogaster) | M14.A10 | - |
| CG18585 g.p. (Drosophila melanogaster) | M14.A11 | - |
| CG14820 g.p. (Drosophila melanogaster) | M14.A12 | - |
| CG8564 g.p. (Drosophila melanogaster) | M14.A13 | - |
| CG8563 g.p. (Drosophila melanogaster) | M14.A14 | - |
| CG8562 g.p. (Drosophila melanogaster) | M14.A15 | - |
| CG18417 g.p. (Drosophila melanogaster) | M14.A16 | - |
| CG8539 g.p. (Drosophila melanogaster) | M14.A17 | - |
| CG3108 g.p. (Drosophila melanogaster) | M14.A18 | - |
| CG3097 g.p. (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 homologues | non-peptidase homologue | - |
| Subfamily M14A unassigned peptidases | unassigned | - |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| carboxypeptidase N | M14.004 | Yes |
| carboxypeptidase E | M14.005 | - |
| carboxypeptidase M | M14.006 | Yes |
| metallocarboxypeptidase D peptidase unit 1 | M14.011 | Yes |
| metallocarboxypeptidase Z | M14.012 | - |
| metallocarboxypeptidase D peptidase unit 2 | M14.016 | - |
| CPG70 carboxypeptidase (Porphyromonas gingivalis) | M14.023 | - |
| EGL-21 peptidase | M14.033 | - |
| murein peptide amidase MpaA | M14.034 | Yes |
| protein Silver domain 1 | M14.037 | Yes |
| metallocarboxypeptidase D non-peptidase unit | M14.950 | Yes |
| aortic carboxypeptidase-like protein | M14.951 | - |
| carboxypeptidase-like protein X2 | M14.953 | - |
| inactive carboxypeptidase-like protein X2 (Homo sapiens) | 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 | - |
| Subfamily M14B non-peptidase homologues | non-peptidase homologue | - |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| gamma-D-glutamyl-(L)-meso-diaminopimelate peptidase I | M14.008 | - |
| Subfamily M14C non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M14C unassigned peptidases | unassigned | - |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| carboxypeptidase-like protein X1;CPX-1 g.p. (Mus musculus) | M14.015 | - |
| cytosolic carboxypeptidase 5 | M14.025 | - |
| cytosolic carboxypeptidase 3 | M14.026 | - |
| cytosolic carboxypeptidase 6 | M14.027 | - |
| cytosolic carboxypeptidase 1 | M14.028 | - |
| cytosolic carboxypeptidase 2 | M14.029 | - |
| cytosolic carboxypeptidase 4 | M14.030 | - |
| insect gut carboxypeptidase-2 | M14.031 | - |
| insect gut carboxypeptidase-3 | M14.032 | Yes |
| CPX2 protein (Mus musculus) | M14.036 | - |
| metallocarboxypeptidase CPX-1 (Homo sapiens) | M14.039 | - |
| subfamily M14D nonpeptidase homologue | M14.954 | - |
| CG11428 g.p. (Drosophila melanogaster) | M14.A21 | - |
| ccpp-6 g.p. (Caenorhabditis elegans) | M14.A31 | - |
| Cg31019-pa (Drosophila melanogaster) | M14.A32 | - |
| PFA0170c g.p. (Plasmodium falciparum) | M14.A35 | - |
| cytosolic carboxypeptidase-1 (Caenorhabditis elegans) | M14.A36 | - |
| Subfamily M14D non-peptidase homologues | non-peptidase homologue | Yes |
| Subfamily M14D unassigned peptidases | unassigned | - |
| Subfamily M14D unassigned peptidases | unassigned | Yes |
|
Peptidases not assigned to subfamily
|
| Peptidases and Homologues |
MEROPS ID |
Structure |
| PGP1 D,L-carboxypeptidase (Campylobacter jejuni) | M14.038 | - |
| Family M14 non-peptidase homologues | non-peptidase homologue | - |
| Family M14 unassigned peptidases | unassigned | Yes |
