InterPro domain: IPR023358

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role. Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site [ 1 ]. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [ 2 ].

This group of metallopeptidases belong to the MEROPS peptidase family M18, (clan MH). The proteins have two catalytic zinc ions at the active site, bound by His/Asp, Asp, Glu, Asp/Glu and His. The catalysed reaction involves the release of an N-terminal aminoacid, usually neutral or hydrophobic, from a polypeptide [ 2 ].

The type example is aminopeptidase I from Saccharomyces cerevisiae (Baker's yeast), the sequence of which has been deduced, and the mature protein shown to consistof 469 amino acids [ 2 ]. A 45-residue presequence contains bothpositively- and negatively-charged and hydrophobic residues, which could be arrangedin an N-terminal amphiphilic alpha-helix [ 3 ]. The presequence differs fromsignal sequences that direct proteins across bacterial plasma membranes andendoplasmic reticulum or into mitochondria. It is unclear how this uniquepresequence targets aminopeptidase I to yeast vacuoles, and how thissorting utilises classical protein secretory pathways [ 3 ].

This entry represents the beta roll structural domain found in M18 family and aspartyl aminopeptidases.

1. Evolutionary families of metallopeptidases. Meth. Enzymol. 248, 183-228
2. Molecular cloning and sequencing of genomic DNA encoding aminopeptidase I from Saccharomyces cerevisiae. J. Biol. Chem. 264, 6979-83