Mechanistic Investigations of Ketosteroid Isomserase

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Enzymes are the molecules within cells that make the chemical reactions necessary for life happen fast and happen correctly. These reactions govern all aspects of cellular processes, from the extraction of energy from food, to the building of structures needed for constructing cells and organs, to the exquisite control of these processes as an organism experiences different environments and stresses. This research aims tocontribute to the fundamental understanding of enzyme action via investigation of a highly tractable, model enzyme, bacterial ketosteroid isomerase. This enzyme has several features that will allow its study at unprecedented depth and breadth. Specifically, this research entails a finely crafted blend of structural, dynamic and biochemical studies. Furthermore, this enzyme is tractable for chemical synthesis so that changes at the level of individual amino acids can be introduced systematically and thoroughly, without the limitations of the 20 naturally occurring amino acids. Most broadly, a central unanswered question in enzyme mechanism is the role of the protein structure surrounding the active site where catalysis takes place, and this research will provide incisive tests of the properties of the enzyme environment.Understanding how enzymes function is fundamental for understanding life itself. Furthermore, the majority of drug targets are enzymes, so that a deeper fundamental understanding of the action of enzymes may allow researchers to better design potent inhibitors that can act as drugs for numerous disease states. A deep understanding of enzyme action may also provide the information needed to design new enzymes thatcatalyze new and beneficial reactions that can be used in the pharmaceutical and chemical industries.The broader impact of this project involves the training of graduate students in rigorous, quantitative aspects of biological chemistry, a background that will allow these students to contribute in many ways in their individual careers, as teachers, in applied or fundamental research, and in evaluating policy from a scientific standpoint. Further, the basic nature of the research renders it possible for undergraduates to obtain meaningful research experiences. In particular there are plans to ensure the inclusion of underrepresented minorities in this research, an opportunity that may greatly help stimulate the inclusion of such students in the future in the scientific community.