Peptidases are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry. Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.

Families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the catalytic part of an amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule.

Peptidases are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry. Families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; S, serine; T, threonine; and U, unknown. A clan that contains families of more than one type is described as being of type P. The serine, threonine and cysteine peptidases utilise the catalytic part of an amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule.

Aspartic endopeptidases (EC: 3.4.23.-) of vertebrate, fungal and retroviral origin have been characterised [PMID:1455179]. Aspartate peptidases are so named because Asp residues are the ligands of the activated water molecule in all examples where the catalytic residues have been identified, although at least one viral enzyme is believed to have an Asp and an Asn as its catalytic dyad. All or most aspartate peptidases are endopeptidases. These enzymes have been assigned into clans (proteins which are evolutionary related), and further sub-divided into families, largely on the basis of their tertiary structure.

Aspartic endopeptidases (EC: 3.4.23.-) of vertebrate, fungal and retroviral origin have been characterised [PMID:1455179]. Structurally, aspartic endopeptidases are bilobal enzymes, each lobe contributing a catalytic Asp residue, with an extended active site cleft localized between the two lobes of the molecule. One lobe has probably evolved from the other through a gene duplication event in the distant past. In modern-day enzymes, although the three-dimensional structures are very similar, the amino acid sequences are more divergent, except for the catalytic site motif, which is very conserved. The presence and position of disulphide bridges are other conserved features of aspartic peptidases. All or most aspartate peptidases are endopeptidases. These enzymes have been assigned into clans (proteins which are evolutionary related), and further sub-divided into families, largely on the basis of their tertiary structure.

This group of aspartic peptidases belong to MEROPS peptidase family A1 (pepsin family, clan AA). The type example is pepsin A from Homo sapiens.

More than 70 aspartic peptidases, from all from eukaryotic organisms, have been identified. These include pepsins, cathepsins, and renins. 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.

Most members of the pepsin family specifically cleave bonds in peptides that are at least six residues in length, with hydrophobic residues in both the P1 and P1' positions [PMID:7674916]. Crystallography has shown the active site to form a groove across the junction of the two lobes, with an extended loop projecting over the cleft to form an 11-residue flap, which encloses substrates and inhibitors within the active site [PMID:7674916]. Specificity is determined by several hydrophobic residues surrounding the catalytic aspartates, and by three residues in the flap. Cysteine residues are well conserved within the pepsin family, pepsin itself containing three disulphide loops. The first loop is found in all but the fungal enzymes, and is usually around five residues in length, but is longer in barrierpepsin and candidapepsin; the second loop is also small and found only in the animal enzymes; and the third loop is the largest, found in all members of the family, except for the cysteine-free polyporopepsin. The loops are spread unequally throughout the two lobes, suggesting that they formed after the initial gene duplication and fusion event [PMID:7674916].

This family does not include the retroviral nor retrotransposon aspartic proteases which are much smaller and appear to be homologous to the single domain aspartic proteases.