| Name | Peptidase family A2 (retropepsin family) |
|---|
| Family type peptidase | A02.001 - HIV-1 retropepsin (human immunodeficiency virus 1), MEROPS Accession MER0001449 (peptidase unit: 504-599) |
| Content of family | Peptidase family A2 contains endopeptidases. |
| History |
Identifier created: Biochem.J. 290:205-218 (1993)
The retropepsins were discovered in the late 1980"s because of their essential role in the maturation of the human immunodeficiency virus (HIV) responsible for acquired immunodeficiency syndome (AIDS). |
| Catalytic type | Aspartic |
| Active site | Activated water is the nucleophile in peptidases in family A2, as in all of clan AA. The water molecule is bound by two aspartic residues, one from each monomer of the homo-dimeric molecule. The retropepsin monomer also includes a structural element equivalent to the "flap" over the active site cleft in pepsin (A01.001). In pepsin, a tyrosine residue on the flap is important for substrate binding. In the retropepsin dimer, the two flaps form a beta-sheet that interacts with the substrate. |
| Activities and specificities | Peptidases in family A2 are maximally active in the range pH 4-6 (Ido et al., 1991). |
| Inhibitors | No protein inhibitors of the retropepsins are known. Pepstatin inhibits peptidases from families A1 and A2. Potent, small-molecule inhibitors of the retropepsins have been developed for use in the management of AIDS. |
| Molecular structure | The tertiary structure of the Rous sarcoma virus peptidase (A02.015) was solved in 1980 (Misono et al., 1980) and that of HIV-1 retropepsin (A02.001) in 1989 (Miller et al., 1989; Navia et al., 1989). The peptidase contains only beta secondary structural elements. Retropepsins are active only as their homodimers. The monomers are structurally related to one lobe of the pepsin (A01.001) molecule, and family A2 is included in clan AA. Each active site aspartate occurs within a DTG motif, as it does in pepsin. It should be noted, however, that DTG is a commonly-occurring motif and the presence of this motif alone is not evidence that the protein is an aspartic peptidase; for example, the DTG motif also occurs in the subtilisin family (S8). |
| Clan | AA |
| Basis of clan assignment | Protein fold of the peptidase unit for members of this family resembles pepsin, the type example for clan AA. |
| Biological functions | Retropepsin is autolytically released from the gag-pol polyprotein and the peptidase has to dimerize to be active. How this process is initiated is not known, but it may follow release of retropepsin monomers from the viral polyprotein by host peptidases. Similar processes occur in other retroid viruses, including important pathogens such as human T-cell leukemia virus, equine infectious anemia virus, mouse mammary tumor virus and Rous avian sarcoma virus. Homologous proteins are encoded in mammalian genomes, including the product of the human vprt gene and the mouse intracisternal A-particle, but the functions and origins of these are unknown. |
| Pharmaceutical and biotech relevance | The HIV-1 retropepsin has been studied intensively as a target for treatment of AIDS. Amongst the many effective inhibitors of the enzyme that are now marketed as drugs is ritonavir (Kempf et al., 1998). |
| Reviews | Dunn & Rao (2004), and other chapters in the same volume. |
| Statistics for family A2 | Sequences: | 1692 |
| Identifiers: | 52 |
| Identifiers with PDB entries: | 15 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| HIV-1 retropepsin | A02.001 | Yes |
| HIV-2 retropepsin | A02.002 | Yes |
| simian immunodeficiency virus retropepsin | A02.003 | - |
| bovine immunodeficiency virus retropepsin | A02.005 | Yes |
| Visna lentivirus-type retropepsin | A02.006 | Yes |
| feline immunodeficiency virus retropepsin | A02.007 | Yes |
| murine leukemia virus-type retropepsin | A02.008 | Yes |
| Mason-Pfizer leukemia virus retropepsin | A02.009 | Yes |
| mouse mammary tumor virus retropepsin | A02.010 | - |
| human endogenous retrovirus K retropepsin | A02.011 | - |
| bovine leukemia virus retropepsin | A02.013 | Yes |
| intracisternal A-particle retropepsin | A02.016 | - |
| multiple-sclerosis-associated retrovirus retropepsin | A02.019 | - |
| porcine endogenous retrovirus peptidase | A02.020 | - |
| rabbit endogenous retrovirus endopeptidase | A02.024 | - |
| S71-related human endogenous retropepsin | A02.053 | - |
| RTVL-H-type putative peptidase | A02.055 | - |
| human endogenous retrovirus retropepsin homologue 1 | A02.056 | - |
| human endogenous retrovirus retropepsin homologue 2 | A02.057 | - |
| type D-like endogenous retrovirus peptidase (Mus musculus) | A02.060 | - |
| Ulysses retrotransposon retropepsin | A02.061 | - |
| endogenous retrovirus retropepsin pseudogene 1 (Homo sapiens chromosome 14) | A02.P01 | - |
| endogenous retrovirus retropepsin pseudogene 2 (Homo sapiens chromosome 8) | A02.P02 | - |
| endogenous retrovirus retropepsin pseudogene 3 (Homo sapiens chromosome 17) | A02.P03 | - |
| endogenous retrovirus retropepsin pseudogene 5 (Homo sapiens chromosome 12) | A02.P04 | - |
| endogenous retrovirus retropepsin pseudogene 6 (Homo sapiens chromosome 7) | A02.P05 | - |
| endogenous retrovirus retropepsin pseudogene 7 (Homo sapiens chromosome 6) | A02.P06 | - |
| endogenous retrovirus retropepsin pseudogene 8 (Homo sapiens chromosome Y) | A02.P07 | - |
| endogenous retrovirus retropepsin pseudogene 9 (Homo sapiens chromosome 19) | A02.P08 | - |
| endogenous retrovirus retropepsin pseudogene 10 (Homo sapiens chromosome 12) | A02.P09 | - |
| endogenous retrovirus retropepsin pseudogene 11 (Homo sapiens chromosome 17) | A02.P10 | - |
| endogenous retrovirus retropepsin pseudogene 12 (Homo sapiens chromosome 11) | A02.P11 | - |
| endogenous retrovirus retropepsin pseudogene 13 (Homo sapiens chromosome 2 and similar) | A02.P12 | - |
| endogenous retrovirus retropepsin pseudogene 14 (Homo sapiens chromosome 2) | A02.P13 | - |
| endogenous retrovirus retropepsin pseudogene 15 (Homo sapiens chromosome 4) | A02.P14 | - |
| endogenous retrovirus retropepsin pseudogene 16 | A02.P15 | - |
| endogenous retrovirus retropepsin pseudogene 17 (Homo sapiens chromosome 8) | A02.P16 | - |
| endogenous retrovirus retropepsin pseudogene 18 (Homo sapiens chromosome 4) | A02.P17 | - |
| endogenous retrovirus retropepsin pseudogene 19 (Homo sapiens chromosome 16) | A02.P18 | - |
| endogenous retrovirus retropepsin pseudogene 21 (Homo sapiens) | A02.P19 | - |
| endogenous retrovirus retropepsin pseudogene 22 (Homo sapiens chromosome X) | A02.P20 | - |
| Subfamily A2A non-peptidase homologues | non-peptidase homologue | - |
| Subfamily A2A unassigned peptidases | unassigned | Yes |