Aspartate protease

Aspartic proteases are a family of protease enzymes that use an aspartate 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.

Aspartic endopeptidases EC 3.4.23. of vertebrate, fungal and retroviral origin have been characterised^[1]. More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin^[2] and archaean preflagellin have been described^[3][4].

Eukaryotic aspartic proteases include pepsins, cathepsins, and renins. They have a two-domain structure, 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. Each domain contributes 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 disulfide bridges are other conserved features of aspartic peptidases.

Examples

• HIV-1 protease - a major drug-target for treatment of HIV
• Chymosin (or "rennin", with two "n"s)
• Renin (with one "n")
• Cathepsin D
• Pepsin
• Plasmepsin

Mechanism

Proposed mechanism of peptide cleavage by aspartyl proteases^[5]

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.^[5][6] 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.

Subfamilies

• Peptidase A1, beta-site APP cleaving enzyme, BACE IPR009119

Human proteins containing this domain

BACE; BACE1; BACE2; CTSD; CTSE; NAPSA; PGA5; PGC; REN;

Inhibition

Pepstatin is an inhibitor of aspartate proteases.

External links

• MeSH Aspartic+Endopeptidases

See also

• The Proteolysis Map

References

1. ^ Szecsi PB (1992). "The aspartic proteases". Scand. J. Clin. Lab. In vest. Suppl. 210: 5–22. PMID 1455179. 
2. ^ Taylor R K, LaPointe CF (2000). "The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases". J.Biol. Chem. 275 (2): -. PMID 10625704. 
3. ^ Jarrell KF, Ng SY, Chaban B (2006). "Archaeal flagella, bacterial flagella and type IV pili: a comparison of genes and posttranslational modifications". J. Mol. Microbiol. Bio technol. 11 (3): -. PMID 16983194. 
4. ^ Jarrell KF, Bardy SL (2003). "Cleavage of preflagellins by an aspartic acid signal peptidase is essential for flagellation in the archaeon Methanococcus voltae". Mol. Microbiol. 50 (4): 1339–1347. PMID 14622420. 
5. ^ ^{a b} 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. doi:10.1073/pnas.84.20.7009. PMID 3313384. 
6. ^ Brik A, Wong CH (2003). "HIV-1 protease: mechanism and drug discovery". Org. Biomol. Chem. 1 (1): 5–14. doi:10.1039/b208248a. PMID 12929379. 

This article includes text from the public domain Pfam and InterPro IPR000036