Family A1

Family

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

A1A

Summary Holotypes Alignment Tree Genomes Literature

A1B

Summary Holotypes Alignment Tree Genomes Literature

Summary for family A1

NamePeptidase family A1 (pepsin family)
Family type peptidaseA01.001 - pepsin A (Homo sapiens), MEROPS Accession MER0000885 (peptidase unit: 63-388)
Content of familyPeptidase 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 typeAspartic
Active siteThe 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). Exceptionally, in histoaspartic peptidase from Plasmodium falciparum one of the Asp residues is replaced by His (Bannerjee et al., 2002<%[20040510D049]%>) .
Activities and specificitiesThe 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.
InhibitorsPepstatin (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 structureThe 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).
ClanAA
Basis of clan assignmentType family of clan AA.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses -  
Biological functionsMEROPS 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 relevanceDrug 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.
ReviewsJames, 2004
Statistics for family A1Sequences:16037
Identifiers:184
Identifiers with PDB entries:35
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily A1A
Name Peptidase subfamily A1A
Subfamily type peptidase A01.001 - pepsin A (Homo sapiens), MEROPS Accession MER0000885 (peptidase unit: 63-388)
Active site residues D,H94 F,S,Y137 D277 
Statistics Sequences: 12391
Identifiers: 119
Identifiers with PDB entries: 34
Other databases CATH 2.40.70.10
HOMSTRAD asp
HSSP 5pep
INTERPRO IPR001461
PANTHER PTHR13683
PFAM PF00026
PFAM PF14543
SCOP 50646
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
pepsin AA01.001Yes
pepsin BA01.002-
gastricsinA01.003Yes
memapsin-2A01.004Yes
chymosinA01.006Yes
reninA01.007Yes
renin-2A01.008Yes
cathepsin DA01.009Yes
cathepsin EA01.010Yes
penicillopepsinA01.011Yes
rhizopuspepsinA01.012Yes
mucorpepsinA01.013Yes
candidapepsin SAP1A01.014Yes
barrierpepsinA01.015-
aspergillopepsin IA01.016Yes
endothiapepsinA01.017Yes
saccharopepsinA01.018Yes
polyporopepsinA01.019Yes
phytepsinA01.020Yes
plasmepsin (Plasmodium sp.)A01.021Yes
plasmepsin-1A01.022Yes
plasmepsin-2A01.023Yes
peptidase FA01.026-
trichodermapepsinA01.027Yes
embryonic pepsin (Gallus gallus)A01.028-
yapsin-1A01.030Yes
yapsin-2A01.031-
yapsin-3A01.035-
axp peptidase (Yarrowia lipolytica)A01.036-
canditropsinA01.037Yes
candiparapsinA01.038Yes
memapsin-1A01.041Yes
syncephapepsinA01.042-
histoaspartic peptidase (Plasmodium falciparum)A01.043Yes
podosporapepsinA01.044-
nothepsinA01.045-
napsin AA01.046-
pepsin FA01.051-
Mername-AA045 peptidaseA01.052-
necepsin-1A01.053-
tick heme-binding aspartic proteinase (Rhipicephalus microplus)A01.054-
Mername-AA047 peptidaseA01.055Yes
Mername-AA034 peptidaseA01.057-
eimepsinA01.058-
plasmepsin-4A01.059Yes
candidapepsin SAP2A01.060Yes
candidapepsin SAP3A01.061Yes
candidapepsin SAP4A01.062-
candidapepsin SAP5A01.063Yes
candidapepsin SAP6A01.064-
candidapepsin SAP7A01.065-
candidapepsin SAP8A01.066-
candidapepsin SAP9A01.067-
necepsin-2A01.068-
pepsin A4A01.070-
pepsin A5 (Homo sapiens)A01.071-
oryzepsinA01.072Yes
Sapp2p peptidase (Candida parapsilosis)A01.076-
CtsD peptidase (Aspergillus-type)A01.077-
CnAP1 peptidaseA01.078-
PepAa peptidaseA01.079-
PepAb peptidaseA01.080-
PepAc peptidaseA01.081-
SA76 peptidase (Trichoderma sp.)A01.082-
hCG1733572 (Homo sapiens)-type putative peptidaseA01.083-
candidapepsin SAP10A01.085-
toxomepsin 1A01.087-
pepsin (fish)A01.088-
pregnancy-associated glycoprotein 2A01.089-
CAD2 peptidase (Musca domestica)A01.092-
CAD3 peptidase (Musca domestica)A01.093-
pregnancy-associated glycoprotein 12A01.094-
shewasin AA01.095-
chlapsinA01.096-
ASP5 g.p. (Toxoplasma gondii)A01.098-
cockroach allergenA01.950Yes
pregnancy-associated glycoprotein 1A01.971-
family A1 unassigned non-peptidase homologueA01.973-
CG31926 protein (Drosophila melanogaster)A01.A01-
At1g62290 (Arabidopsis thaliana)A01.A02-
At4g04460 (Arabidopsis thaliana)A01.A03-
CG17283-RA (Drosophila melanogaster)A01.A04-
At1g69100 (Arabidopsis thaliana)A01.A32-
At4g22050 (Arabidopsis thaliana)A01.A33-
yapsin-6 (Saccharomyces cerevisiae)A01.A62-
CG13374 protein (Drosophila melanogaster)A01.A63-
CG10104 g.p.(Drosophila melanogaster)A01.A64-
CG5863 protein (Drosophila melanogaster)A01.A65-
CG5860 protein (Drosophila melanogaster)A01.A66-
CG31928 protein (Drosophila melanogaster)A01.A67-
CG10872 protein (Drosophila melanogaster)A01.A68-
asp-3 g.p. (Caenorhabditis elegans)A01.A69-
K10C2.3 protein (Caenorhabditis elegans)A01.A70-
asp-6 g.p. (Caenorhabditis elegans)A01.A71-
F59D6.3 protein (Caenorhabditis elegans)A01.A72-
Y39B6B.h protein (Caenorhabditis elegans)A01.A73-
F21F8.4 protein (Caenorhabditis elegans)A01.A74-
C11D2.2 g.p. (Caenorhabditis elegans)A01.A75-
C15C8.3 g.p. (Caenorhabditis elegans)A01.A76-
F59D6.2 g.p. (Caenorhabditis elegans)A01.A77-
CG17134 protein (Drosophila melanogaster)A01.A78-
CG6508 protein (Drosophila melanogaster)A01.A79-
CG10872 protein (Drosophila melanogaster)A01.A81-
Ceasp1 protein (Caenorhabditis elegans)A01.A82-
F28A12.4 g.p. (Caenorhabditis elegans)A01.A83-
asp-2 g.p. (Caenorhabditis elegans)A01.A84-
Y39B6A.23 g.p. (Caenorhabditis elegans)A01.A85-
Y39B6A.24 g.p. (Caenorhabditis elegans)A01.A86-
ZK384.3 g.p. domain 1 (Caenorhabditis elegans)A01.A87-
DDB_0205773 (Dictyostelium discoideum)A01.A88-
DDB_G0279411 (Dictyostelium discoideum)A01.A89-
DDB_G0277581 (Dictyostelium discoideum)A01.A90-
Sxa1 peptidase (Schizosaccharomyces pombe)A01.A91-
DDB_G0270722 g.p. (Dictyostelium discoideum)A01.A92-
PF3D7_0808200 g.p. (Plasmodium falciparum)A01.A93-
SCRG_02223 g.p. (Saccharomyces cerevisiae)A01.A94-
PF14_0281 g.p. (Plasmodium falciparum)A01.A95-
napsin B pseudogeneA01.P01-
CYMP g.p. (Homo sapiens)A01.P02-
subfamily A1A non-peptidase homologuesnon-peptidase homologue-
subfamily A1A unassigned peptidasesunassignedYes
Subfamily A1B
Name Peptidase subfamily A1B
Subfamily type peptidase A01.040 - nepenthesin (Nepenthes gracilis), MEROPS Accession MER0031323 (peptidase unit: 75-437)
Active site residues D113 Y174 D315 
Statistics Sequences: 3503
Identifiers: 61
Identifiers with PDB entries: 1
Other databases INTERPRO IPR001461
PANTHER PTHR13683
PFAM PF00026
PFAM PF14541
PFAM PF14543
SCOP 50646
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
nepenthesinA01.040-
CND41 peptidaseA01.050-
CDR1 peptidase (Arabidopsis-type)A01.069-
nucellinA01.073-
PCS1 peptidaseA01.074-
plasmepsin-5 (Plasmodium sp.)A01.075-
S5 peptidase (Oryza sativa)A01.086-
xylanase inhibitor precursorA01.974Yes
At1g01300 (Arabidopsis thaliana)-type peptidaseA01.A05-
At1g25510 (Arabidopsis thaliana)-type peptidaseA01.A06-
At1g79720 (Arabidopsis thaliana)-type peptidaseA01.A07-
At2g42980 (Arabidopsis thaliana)A01.A08-
ASPG1 peptidaseA01.A09-
At3g20015 (Arabidopsis thaliana)-type peptidaseA01.A10-
At3g25700 (Arabidopsis thaliana)-type peptidaseA01.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 peptidaseA01.A23-
At1g44130 (Arabidopsis thaliana)-type peptidaseA01.A24-
At1g49050 (Arabidopsis thaliana)-type peptidaseA01.A25-
At1g77480 (Arabidopsis thaliana)A01.A26-
At4g33490 (Arabidopsis thaliana)-type peptidaseA01.A27-
At1g66180 (Arabidopsis thaliana)A01.A28-
At2g39710 (Arabidopsis thaliana)-type peptidaseA01.A29-
At3g12700 (Arabidopsis thaliana)-type peptidaseA01.A30-
At5g37540 (Arabidopsis thaliana)A01.A31-
At1g05840 (Arabidopsis thaliana)-type peptidaseA01.A34-
At1g08210 (Arabidopsis thaliana)A01.A35-
At1g09750 (Arabidopsis thaliana)-type peptidaseA01.A36-
At1g65240 (Arabidopsis thaliana)A01.A37-
At2g17760 (Arabidopsis thaliana)-type peptidaseA01.A38-
At2g23945 (Arabidopsis thaliana)-type peptidaseA01.A39-
At2g36670 (Arabidopsis thaliana)-type peptidaseA01.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 peptidaseA01.A47-
At3g54400 (Arabidopsis thaliana)-type peptidaseA01.A48-
At4g12920 (Arabidopsis thaliana)A01.A49-
At4g16560 (Arabidopsis thaliana)-type peptidaseA01.A50-
At4g30030 (Arabidopsis thaliana)A01.A51-
At4g30040 (Arabidopsis thaliana)A01.A52-
At4g35880 (Arabidopsis thaliana)-type peptidaseA01.A53-
At5g07030 (Arabidopsis thaliana)-type peptidaseA01.A54-
At5g10080 (Arabidopsis thaliana)-type peptidaseA01.A55-
At5g22850 (Arabidopsis thaliana)-type peptidaseA01.A56-
At5g36260 (Arabidopsis thaliana)A01.A58-
At5g43100 (Arabidopsis thaliana)-type peptidaseA01.A59-
At5g45120 (Arabidopsis thaliana)-type peptidaseA01.A60-
subfamily A1B non-peptidase homologuesnon-peptidase homologue-
subfamily A1B unassigned peptidasesunassigned-
Peptidases not assigned to subfamily
Peptidases and Homologues MEROPS ID Structure
Yps1 protein (Schizosaccharomyces pombe)A01.056-
yolk cathepsin (Boophilus sp.)A01.084-
GPI-anchored aspartic peptidase (Saccharomyces-type)A01.097-
At5g24820-type peptidaseA01.A57-
family A1 non-peptidase homologuesnon-peptidase homologue-
family A1 unassigned peptidasesunassigned-