| Name | Peptidase family A1 (pepsin family) |
|---|
| Family type peptidase | A01.001 - pepsin A (Homo sapiens), MEROPS Accession MER0000885 (peptidase unit: 63-388) |
| Content of family | Peptidase family A1 contains endopeptidases, most of which are most active at acidic pH. |
| History |
Identifier created: Biochem.J. 290:205-218 (1993)
Family A1 contains peptidases that were formerly known as 'acid proteinases' or 'carboxyl proteinases'. The type peptidase is pepsin A (A01.001), which has long been known for its contribution to proteolysis of food proteins in the vertebrate stomach, and was the second enzyme to be crystallised (Northrop, 1930). The existence of a family of homologous peptidases became clear with the elucidation of the amino acid sequences of cathepsin D (A01.009), penicillopepsin (A01.011) and others. |
| Catalytic type | Aspartic |
| Active site | The catalytic centre is formed by two Asp residues that activate a water molecule, and this mediates the nucleophilic attack on the peptide bond (James, 2004). |
| Activities and specificities | The great majority of peptidases in family A1 are most active at acid pH, although some such as renin (A01.007) are also active at neutral pH. No cofactors are required.
All the peptidases in family A1 (and indeed in clan AA) are endopeptidases. Specificity is typically for residues with large hydrophobic sidechains on either side of the scissile bond, but several members have more restricted specificities that allow protein-processing functions (see below).
The enzymes are mostly secreted from cells as inactive proenzymes that activate autocatalytically at acidic pH. |
| Activities and specificities | The great majority of peptidases in family A1 are most active at acid pH, although some such as renin (A01.007) are also active at neutral pH. No cofactors are required.
All the peptidases in family A1 (and indeed in clan AA) are endopeptidases. Specificity is typically for residues with large hydrophobic sidechains on either side of the scissile bond, but several members have more restricted specificities that allow protein-processing functions (see below).
The enzymes are mostly secreted from cells as inactive proenzymes that activate autocatalytically at acidic pH. |
| Inhibitors | Pepstatin (Marciniszyn et al., 1976) is the most widely used inhibitor of peptidases in family A1. It is a tight-binding, reversible inhibitor. Affinity chromatography on immobilised pepstatin, with elution at neutral to alkaline pH, represents a somewhat general method of purification for the mature enzymes in family A1. Aspartic peptidases in some other families (e.g. A2) are also inhibited by pepstatin, but most peptidases of other catalytic types are unaffected. Amongst the few known protein inhibitors of peptidases in family A1 are the Ascaris pepsin inhibitor (I33.001), potato cathepsin D inhibitor (I03.002), and the highly-selective saccharopepsin inhibitor (I34.001). |
| Molecular structure | The peptidases in the family have evidently evolved by a gene duplication, and the two catalytic Asp residues, like the lobes in which they are contained, are homologous (Tang, 2004). The amino acid sequences show signal peptides and propeptides except for bacterial homologues which also lack disulfide bridges and are probably cytoplasmic (Rawlings & Bateman, 2009). Many three-dimensional structures have been described. The catalytic site is located between the two lobes of the molecules, and a 'flap' structure containing a conserved Tyr residue controls specificity (James, 2004; Hong & Tang, 2004). Several of the peptidases are glycosylated (e.g. cathepsin D, A01.009) and a few are membrane-bound (memapsin-1 and memapsin-2, A01.041 and A01.004, respectively). Some family A1 peptidases from plants (e.g. phytepsin, A01.020) contain inserted saposin-like sequences, and the effects of these on enzymatic activity have been investigated (Payie et al., 2003). The secreted proteins in subfamily A usually have three conserved disulfide bridges, whereas in subfamily B there are six, and the unusual stability of nepenthesin (A01.040) to a wide pH range has been attributed to these disulfide bridges (Takahashi et al., 2005). |
| Clan | AA |
| Basis of clan assignment | Type family of clan AA. |
| Biological functions | MEROPS Release 7.4 recognised about 70 peptidases in the family, all from eukaryotic organisms, including ten homologues in the human genome. The enzymes are synthesised with signal peptides, and the proenzymes are secreted or passed into the lysosomal/endosomal system, where acidification leads to autocatalytic activation. We speculate that an early function may have been the external digestion of food proteins by saprophytic organisms. Homologues that show restricted specificity conducive to limited proteolysis include renin (A01.007) and yapsin 1 (A01.030). The functions of homologues in plants are less clear. Nepenthesin (A01.040) from the insectivorous pitcher-plant, has a nutritional function comparable to that of pepsin; nucellin (A01.073) may be involved in the programmed cell-death that occurs at the base of the pistil (the megasporangium or nucellus) following fertilization of the ovule and development of the embryo (Chen & Foolad, 1997). |
| Pharmaceutical and biotech relevance | Drug targets in the family include renin (A01.007) for hypertension, memapsin 2 (A01.004) is a beta-secretase in Alzheimer's disease, and the plasmepsins (A01.021, A01.022, A01.023) for malaria.
Chymosin (A01.006), rhizopuspepsin (A01.012) and some forms of phytepsin (A01.020) have been used to coagulate casein in cheese-making. |
| Reviews | James, 2004 |
| Statistics for family A1 | Sequences: | 20416 |
| Identifiers: | 185 |
| Identifiers with PDB entries: | 38 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| nepenthesin | A01.040 | - |
| CND41 peptidase | A01.050 | - |
| CDR1 peptidase (Arabidopsis-type) | A01.069 | - |
| nucellin | A01.073 | - |
| PCS1 peptidase | A01.074 | - |
| plasmepsin-5 (Plasmodium sp.) | A01.075 | Yes |
| S5 peptidase (Oryza sativa) | A01.086 | - |
| toxomepsin 1 | A01.087 | - |
| xylanase inhibitor precursor | A01.974 | Yes |
| At1g01300 (Arabidopsis thaliana)-type peptidase | A01.A05 | - |
| At1g25510 (Arabidopsis thaliana)-type peptidase | A01.A06 | - |
| At1g79720 (Arabidopsis thaliana)-type peptidase | A01.A07 | - |
| At2g42980 (Arabidopsis thaliana) | A01.A08 | - |
| ASPG1 peptidase | A01.A09 | - |
| At3g20015 (Arabidopsis thaliana)-type peptidase | A01.A10 | - |
| At3g25700 (Arabidopsis thaliana)-type peptidase | A01.A11 | - |
| At3g59080 (Arabidopsis thaliana) | A01.A12 | - |
| At3g61820 (Arabidopsis thaliana) | A01.A13 | - |
| At5g10760 (Arabidopsis thaliana) | A01.A14 | - |
| At5g10770 (Arabidopsis thaliana) | A01.A15 | - |
| At1g31450 (Arabidopsis thaliana) | A01.A16 | - |
| At1g64830 (Arabidopsis thaliana) | A01.A17 | - |
| At2g28010 (Arabidopsis thaliana) | A01.A18 | - |
| At2g28030 (Arabidopsis thaliana) | A01.A19 | - |
| At2g28040 (Arabidopsis thaliana) | A01.A20 | - |
| At2g28220 (Arabidopsis thaliana) | A01.A21 | - |
| At2g35615 (Arabidopsis thaliana) | A01.A22 | - |
| At3g02740 (Arabidopsis thaliana)-type peptidase | A01.A23 | - |
| At1g44130 (Arabidopsis thaliana)-type peptidase | A01.A24 | - |
| At1g49050 (Arabidopsis thaliana)-type peptidase | A01.A25 | - |
| At1g77480 (Arabidopsis thaliana) | A01.A26 | - |
| At4g33490 (Arabidopsis thaliana)-type peptidase | A01.A27 | - |
| At1g66180 (Arabidopsis thaliana) | A01.A28 | - |
| At2g39710 (Arabidopsis thaliana)-type peptidase | A01.A29 | - |
| At3g12700 (Arabidopsis thaliana)-type peptidase | A01.A30 | - |
| At5g37540 (Arabidopsis thaliana) | A01.A31 | - |
| At1g69100 (Arabidopsis thaliana) | A01.A32 | - |
| At1g05840 (Arabidopsis thaliana)-type peptidase | A01.A34 | - |
| At1g08210 (Arabidopsis thaliana) | A01.A35 | - |
| At1g09750 (Arabidopsis thaliana)-type peptidase | A01.A36 | - |
| A39 g.p. (Arabidopsis thaliana) | A01.A37 | - |
| At2g17760 (Arabidopsis thaliana)-type peptidase | A01.A38 | - |
| At2g23945 (Arabidopsis thaliana)-type peptidase | A01.A39 | - |
| At2g36670 (Arabidopsis thaliana)-type peptidase | A01.A40 | - |
| At3g42550 (Arabidopsis thaliana) | A01.A41 | - |
| At3g50050 (Arabidopsis thaliana) | A01.A42 | - |
| At3g51330 (Arabidopsis thaliana) | A01.A43 | - |
| At3g51340 (Arabidopsis thaliana) | A01.A44 | - |
| At3g51350 (Arabidopsis thaliana) | A01.A45 | - |
| At3g51360 (Arabidopsis thaliana) | A01.A46 | - |
| At3g52500 (Arabidopsis thaliana)-type peptidase | A01.A47 | - |
| At3g54400 (Arabidopsis thaliana)-type peptidase | A01.A48 | - |
| At4g12920 (Arabidopsis thaliana) | A01.A49 | - |
| At4g16560 (Arabidopsis thaliana)-type peptidase | A01.A50 | - |
| At4g30030 (Arabidopsis thaliana) | A01.A51 | - |
| At4g30040 (Arabidopsis thaliana) | A01.A52 | - |
| At4g35880 (Arabidopsis thaliana)-type peptidase | A01.A53 | - |
| At5g07030 (Arabidopsis thaliana)-type peptidase | A01.A54 | - |
| At5g10080 (Arabidopsis thaliana)-type peptidase | A01.A55 | - |
| At5g22850 (Arabidopsis thaliana)-type peptidase | A01.A56 | - |
| A36 g.p. (Arabidopsis thaliana) | A01.A58 | - |
| At5g43100 (Arabidopsis thaliana)-type peptidase | A01.A59 | - |
| At5g45120 (Arabidopsis thaliana)-type peptidase | A01.A60 | - |
| Subfamily A1B non-peptidase homologues | non-peptidase homologue | Yes |
| Subfamily A1B unassigned peptidases | unassigned | - |
