Structure and function of the methionine aminopeptidases.
The removal of the N-terminal methionine from proteins and peptides is dependent upon a novel class of proteases typified by the dinuclear metalloenzyme methionine aminopeptidase from Escherichia coli (eMetAP). Substantial progress has recently been made in determining the structures of several members of this family. The identification of human MetAP as the target of putative 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-state analogs and reaction products has led to a rationalization of the substrate specificity and suggested the presumed catalytic mechanism. The conservation of key active site residues and ligand interactions between the MetAPs and other enzyme of the same fold suggest that avoidance of cross-reactivity may be an important consideration in the design of inhibitors directed toward a single member of the family.
Lowther
W T
WT
Institute of Molecular Biology, Howard Hughes Medical Institute and Department of Physics, University of Oregon, Eugene, OR 97403-1229, USA.
Matthews
B W
BW
D000626:Aminopeptidases / Q000737:chemistry* / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000737:chemistry; D001665:Binding Sites; D003510:Cyclohexanes; D015195:Drug Design; D004492:Edetic Acid; D004926:Escherichia coli; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry; D008670:Metals; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry*; D017510:Protein Folding; D012717:Sesquiterpenes / Q000737:chemistry; D013379:Substrate Specificity
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D008670:Metals; D011480:Protease Inhibitors; D012717:Sesquiterpenes; C002781:ovalicin; C026211:fumagillin; D004492:Edetic Acid; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases; C022750:X-Pro aminopeptidase; D007930:Leucine; C012211:ubenimex