Structure and function of the methionine aminopeptidases

The removal of the N-terminal methionine from proteins and peptides is depe ndent upon a novel class of proteases typified by the dinuclear metalloenzy me methionine aminopeptidase from Escherichia coli (eMetAP). Substantial pr ogress has recently been made in determining the structures of several memb ers of this family. The identification of human MetAP as the target of puta tive anti-cancer drugs reiterates the importance of this Family of enzymes. Determination of the modes of binding to E. coli MetAP of a substrate-like bestatin-based inhibitor, as well as phosphorus-containing transition-stat e analogs and reaction products has led to a rationalization of the substra te specificity and suggested the presumed catalytic mechanism. The conserva tion of key active site residues and ligand interactions between the MetAPs and other enzyme of the same fold suggest that avoidance of cross-reactivi ty may be an important consideration in the design of inhibitors directed t oward a single member of the family. (C) 2000 Elsevier Science B.V. All rig hts reserved.