Molecular Mechanism of Enantiorecognition by Esterases

摘要

One of the most significant trends in the pharmaceutical industry is the increasing presence of single-isomer forms of chiral drugs. Annual sales of enantiopure drugs have reached $35 billion. This creates special demands for novel enantio-selective synthetic technologies. Biotransformations constitute a frequently used technique, but direct applications of highly enantioselective, stable, and cheap enzymes offer an attractive alternative. Esterases, including both interfacially activated lipases and short fatty acid acylhydrolases, are particularly popular among pharmaceutical chemists; for example, these enzymes are used in the preparation of the blood pressure drugs cilazapril and naltiazem, the preparation of the antiinflammatory drug ketorolac, and the synthesis of the C13 side chain of the antitumor agent taxol. To date, the mechanism of enantio-recognition by these enzymes was inferred from substrate mapping, and the resulting empirical rules were used to predict which enantiomer of a secondary alcohol will be a fast-reacting species. We here propose a general model for enantiorecognition by esterases based on several newly determined crystal structures of these enzymes. We show that regardless of their tertiary fold, esterases carry out a nucleophilic attack on the si face of the ester bond.