| Abstract
| - β-Lactam inhibitors of transpeptidase enzymes involved in cell wall biosynthesis remain amongthe most important therapeutic agents in clinical use. β-Lactams have more recently been developed asinhibitors of serine proteases including elastase. All therapeutically useful β-lactam inhibitors operatevia mechanisms resulting in the formation of hydrolytically stable acyl−enzyme complexes. Presently,it is difficult to predict which β-lactams will form stable acyl−enzyme complexes with serine enzymes.Further, the factors that result in the seemingly special nature of β-lactams versus other acylating agentsare unclearif indeed they exist. Here we present the 1.6 Å resolution crystal structure of a stable acyl−enzyme complex formed between porcine pancreatic elastase and a representative monocyclic β-lactam,which forms a simple acyl−enzyme. The structure shows that the ester carbonyl is not located withinthe oxyanion hole and the “hydrolytic” water is displaced. Combined with additional kinetic and massspectrometric data, the structure allows the rationalization of the low degree of hydrolytic lability observedfor the β-lactam-derived acyl−enzyme complex.
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