Enzymes in organic synthesis. Present and future

Abstract

The usefulness and practicality of enzymes as chiral catalysts in organic synthesis are now well documented, with their applications in creating enantiomerically pure synthons for the asymmetric synthesis of important natural products of academic and pharmaceutical interest being particularly important. Enzyme groups of proven value in this regard are the esterases and the oxidoreductases. The types of chiral synthon preparation opportunities that such enzymes offer are illustrated, together with their simple-to-use active site models. However, despite the widespread exploitation of enzymes for synthetic purposes in both academic and industrial applications, little is known about the factors that determine enzyme specificity, while the spectrum of unnatural substrate structures that synthetically useful enzymes are required to handle continues to broaden rapidly. It is therefore becoming essential to delineate the enzyme-substrate interactions that regulate structural specificity and stereospecificity in order to facilitate the identification of the enzymes best suited to transforming new substrate structures into the desired chiral synthons. Similar information is of medicinal value in designing inhibitors of enzymes involved in diseases. Some illustrative strategies for probing enzyme specificities in both these categories arc presented. Natural enzymes cannot hope to accept all structures of synthetic chemical interest, nor always to transform them stereospecifically into the desired enantiomerically pure materials needed for synthesis. Thus, in the future it will become necessary to develop the capability to alter the specificities of enzymes in a controlled manner. These goals are being addressed by protein engineering. Illustrative results of such approaches to effect controlled changes of the specificity are described, using an L-lactate dehydrogenase as a representative oxidoreductases.