Enzyme Mechanisms, Models, and Mimics

Abstract

Abstract“One of the great intellectual challenges presented to Science by Nature is a proper understanding of how enzymes work. At one level we can ‘explain’ enzyme catalysis—what an enzyme does is bind, and thus stabilize, selectively the transition state for a particular reaction.A. R. Fersht, Enzyme Structure and Mechanism, 2nd ed., Freeman, New York, 1985. But our current level of understanding fails the more severe, practical test—that of designing and making artificial enzyme systems with catalytic efficiencies which rival those of natural enzymes.” This was the introduction to a recent Highlight in Angewandte Chemie, A. J. Kirby, Angew. Chem. 1994, 106, 573–576; Angew. Chem. Int. Ed. Engl. 1994, 33, 551–553. prompted by the appearance of a paper that appeared to defy established ideas, by claiming artificial enzyme systems that did indeed attain catalytic efficiency rivaling that of natural enzymes. The “Pepzymes” of Atassi and ManshouriM. Z. Atassi, T. Manshouri, Proc. Natl. Acad. Sci. USA 1993, 90, 8282–8286. were relatively small (29‐residue) peptides modeled on the active site structures of trypsin and chymotrypsin by “surface simulation.” One was claimed to hydrolyze the simple trypsin “substrate” N‐tosyl‐L‐arginine methyl ester with kcat and Km values comparable to those of the native enzyme, and also to hydrolyze the peptide bonds of test proteins to give comparable peptide profiles. This extraordinary result provoked as much skepticism as excitement, and several groups tried to reproduce the results. They failed, comprehensively., D. R. Corey, M. A. Phillips, Proc. Natl. Acad. Sci. USA 1994, 91, 4106–4109. Some specific reasons why this failure came as no surprise have been summarized by Matthews et al.J. A. Wells, W. J. Fairbrother, J. Otlewski, M. Lagowski, J. Burnier, Proc. Natl. Acad. Sci. USA 1994, 91, 4110–4114. This review examines the problems involved in the design of enzyme mimics in more general terms, with the emphasis specifically on the efficiency of catalysis.