Ph.D. University of California, Berkeley 1968; B.S. Brown University 1965
The research in the our laboratory is concerned with bioorganic chemistry and mechanisms of enzymatic catalysis. Our current interest is primarily with the mechanism of enzymatic catalysis of proton transfer reactions involving protons bound to carbon atoms. These reactions are an integral part of the mechanism of action of many enzymes.
In order to investigate the methods by which enzymes can catalyze these proton transfers, we examine both enzymatic and nonenzymatic reactions, enabling a direct comparison to be made between the two systems. The primary enzymatic system of interest is 3-Oxo-D5-steroid isomerase (KSI). This enzyme is one of the most active enzymes known and mechanistically involves a sequence of two proton transfers. We utilize a variety of techniques to investigate the detailed mechanism of this reaction, including site-directed mutagenesis (using both natural and unnatural amino acids), fluorescence, kinetics and NMR structural determinations. Nonenzymatic proton transfer reactions are investigated using substrates of KSI in aqueous solution with various small molecule catalysts. In addition to these systems, potential artificial enzymes are being constructed using the knowledge gained from the above experiments.