Aspartic acid proteases
|Eukaryotic aspartyl protease|
Aspartyl proteases are a family of eukaryotic protease enzymes that utilize an aspartic acid residue for catalysis of their peptide substrates. In general, they have two highly-conserved aspartates in the active site and are optimally active at acidic pH. Nearly all known aspartyl proteases are inhibited by pepstatin.
Eukaryotic aspartic proteases include pepsins, cathepsins, and renins. They have a two-domain structure, probably arising from ancestral duplication. Retroviral and retrotransposon proteases (Pfam PF00077) are much smaller and appear to be homologous to a single domain of the eukaryotic aspartyl proteases.
- HIV-1 protease - a major drug-target for treatment of HIV
- Chymosin (or "rennin", with two "n"s)
- Renin (with one "n")
- Cathepsin D
While a number of different mechanisms for aspartyl proteases have been proposed, the most widely accepted is a general acid-base mechanism involving coordination of a water molecule between the two highly-conserved aspartate residues. One aspartate activates the water by abstracting a proton, enabling the water to attack the carbonyl carbon of the substrate scissile bond, generating a tetrahedral oxyanion intermediate. Rearrangement of this intermediate leads to protonation of the scissile amide.
Human proteins containing this domain
- Suguna K, Padlan EA, Smith CW, Carlson WD, Davies DR (1987). "Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action". Proc. Natl. Acad. Sci. U.S.A. 84 (20): 7009–13. PMID 3313384.
- Brik A, Wong CH (2003). "HIV-1 protease: mechanism and drug discovery". Org. Biomol. Chem. 1 (1): 5–14. PMID 12929379.
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