Pathways & interactions
Aspartic peptidase A1 family (IPR001461)
Short name: Aspartic_peptidase_A1
Peptidase family A1, also known as the pepsin family, contains peptidases with bilobed structures [PMID: 2115088, PMID: 2115087]. The two domains most probably evolved from the duplication of an ancestral gene encoding a primordial domain [PMID: 24179]. The active site is formed from an aspartic acid residue from each domain. Each aspartic acid occurs within a motif with the sequence D(T/S)G(T/S). Exceptionally, in the histoaspactic peptidase from Plasmodium falciparum, one of the Asp residues is replaced by His [PMID: 11782538]. A third essential residue, Tyr or Phe, is found on the N-terminal domain only in a beta-hairpin loop known as the "flap"; this residue is important for substrate binding, and most members of the family have a preference for a hydrophobic residue in the S1 substrate binding pocket. Most members of the family are active at acidic pH, but renin is unusually active at neutral pH. Family A1 peptidases are found predominantly in eukaryotes (but examples are known from bacteria [PMID: 19758436, PMID: 21749650]). Currently known eukaryotic aspartyl peptidases and homologues include the following:
- Vertebrate gastric pepsins A (EC:18.104.22.168), gastricsin (EC:22.214.171.124, also known pepsin C), chymosin (EC:126.96.36.199; formerly known as rennin), and cathepsin E (EC: 188.8.131.52). Pepsin A is widely used in protein sequencing because of its limited and predictable specificity. Chymosin is used to clot milk for cheese making.
- Lysosomal cathepsin D (EC:184.108.40.206).
- Renin (EC:220.127.116.11) which functions in control of blood pressure by generating angiotensin I from angiotensinogen in the plasma.
- Memapsins 1 (EC:18.104.22.168; also known as BACE 2) and 2 (EC:22.214.171.124; also known as BACE) are membrane-bound and are able to perform one of the two cleavages (the beta-cleavage, hence they are also known as beta-secretases) in the beta-amyloid precursor to release the the amyloid-beta peptide, which accumulates in the plaques of Alzheimer's disease patients.
- Fungal peptidases such as aspergillopepsin A (EC:126.96.36.199), candidapepsin (EC:188.8.131.52), mucorpepsin (EC:184.108.40.206; also known as Mucor rennin), endothiapepsin (EC:220.127.116.11), polyporopepsin (EC:18.104.22.168), and rhizopuspepsin (EC:22.214.171.124) are secreted for sapprophytic protein digestion.
- Fungal saccharopepsin (EC:126.96.36.199) (proteinase A) (gene PEP4) is implicated in post-translational regulation of vacuolar hydrolases.
- Yeast barrierpepsin (EC:188.8.131.52) (gene BAR1); a protease that cleaves alpha-factor and thus acts as an antagonist of the mating pheromone.
- Fission yeast Sxa1 may be involved in degrading or processing the mating pheromones [PMID: 1549128].
- In plants, phytepsin (EC:184.108.40.206) degrades seed storage proteins and nepenthesin (EC 220.127.116.11) from a pitcher plant digests insect proteins.
- Plasmepsins (EC:18.104.22.168 and EC:22.214.171.124) from Plasmodium species are important for the degradation of host haemoglobin.
- Non-peptidase homologues where one or more active site residues have been replaced, include mammalian pregnancy-associated glycoproteins, an allergen from a cockroach, and a xylanase inhibitor [PMID: 15166216].
Aspartic peptidases, also known as aspartyl proteases (EC:3.4.23.-), are widely distributed proteolytic enzymes [PMID: 6795036, PMID: 2194475, PMID: 1851433] known to exist in vertebrates, fungi, plants, protozoa, bacteria, archaea, retroviruses and some plant viruses. All known aspartic peptidases are endopeptidases. A water molecule, activated by two aspartic acid residues, acts as the nucleophile in catalysis. Aspartic peptidases can be grouped into five clans, each of which shows a unique structural fold [PMID: 8439290].
- Peptidases in clan AA are either bilobed (family A1 or the pepsin family) or are a homodimer (all other families in the clan, including retropepsin from HIV-1/AIDS) [PMID: 2682266]. Each lobe consists of a single domain with a closed beta-barrel and each lobe contributes one Asp to form the active site. Most peptidases in the clan are inhibited by the naturally occurring small-molecule inhibitor pepstatin [PMID: 4912600].
- Clan AC contains the single family A8: the signal peptidase 2 family. Members of the family are found in all bacteria. Signal peptidase 2 processes the premurein precursor, removing the signal peptide. The peptidase has four transmembrane domains and the active site is on the periplasmic side of the cell membrane. Cleavage occurs on the amino side of a cysteine where the thiol group has been substituted by a diacylglyceryl group. Site-directed mutagenesis has identified two essential aspartic acid residues which occur in the motifs GNXXDRX and FNXAD (where X is a hydrophobic residue) [PMID: 10497172]. No tertiary structures have been solved for any member of the family, but because of the intramembrane location, the structure is assumed not to be pepsin-like.
- Clan AD contains two families of transmembrane endopeptidases: A22 and A24. These are also known as "GXGD peptidases" because of a common GXGD motif which includes one of the pair of catalytic aspartic acid residues. Structures are known for members of both families and show a unique, common fold with up to nine transmembrane regions [PMID: 21765428]. The active site aspartic acids are located within a large cavity in the membrane into which water can gain access [PMID: 23254940].
- Clan AE contains two families, A25 and A31. Tertiary structures have been solved for members of both families and show a common fold consisting of an alpha-beta-alpha sandwich, in which the beta sheet is five stranded [PMID: 10331925, PMID: 10864493].
- Clan AF contains the single family A26. Members of the clan are membrane-proteins with a unique fold. Homologues are known only from bacteria. The structure of omptin (also known as OmpT) shows a cylindrical barrel containing ten beta strands inserted in the membrane with the active site residues on the outer surface [PMID: 11566868].
- There are two families of aspartic peptidases for which neither structure nor active site residues are known and these are not assigned to clans. Family A5 includes thermopsin, an endopeptidase found only in thermophilic archaea. Family A36 contains sporulation factor SpoIIGA, which is known to process and activate sigma factor E, one of the transcription factors that controls sporulation in bacteria [PMID: 21751400].