April 27, 2007
Multidisciplinary approach to discovery of inhibitors of methionine aminopeptidases
Methionine aminopeptidase (MetAP) catalyzes removal of N-terminal methionine from newly synthesized proteins in all types of cells. Inhibitors of MetAPs are of considerable interest as potential antibacterial, antifungal and anticancer agents. All MetAPs require a divalent metal ion such as Mn(II), Fe(II), Co(II) for activity, but it is not certain which of these ions is the most important in cells. Novel MetAP inhibitors with selectivity towards different metalloforms were discovered by high throughput screening, and their inhibition of MetAP was characterized by enzyme kinetics and X-ray structural analysis. These inhibitors are valuable research tools to study catalysis and inhibition of MetAP.