MECHANISTIC STUDY OF RADICALS IN BIOLOGY CATALYSIS

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Life, the most complex and fascinating phenomenon within the purview of man, may be defined in terms of the functional integration of simple structures that are themselves devoid of all of the characteristics of living systems. I believe that understanding the life process in detail involves pinpointing how function arises from structure. My decision to become an academician and to devote myself to the study of bioorganic chemistry reflects this concern in that it will allow me to probe the structures and interactions of biological macro-molecules, and in so doing, provide the basis for further study of their functions both as discrete units and as members of more complex systems. Outlined in this proposal are experiments designed to study a few important enzymes whose mechanism may involve the formation of a radical intermediate. The first system to be investigated is the biosynthesis of 3,6-dideoxyhexoses. Our emphasis will be placed on the mechanistic studies of C-3 deoxygenation leading to the formation of ascarylose which is an important immuno-dominant sugar. The second system to be examined is general acyl-CoA dehydrogenase which catalyzes the first step of beta-oxidation of fatty acids. Our initial effort will be directed toward studying the inactivation of this enzyme by (methylenecyclopropyl)acetyl-CoA which is the causative agent of Jamaican vomiting sickness. The longterm goal of these studies is to establish a complete understanding of the functions of these enzymatic processes as a prerequisite to the rational design of methods to control and mimic their physiological roles. However, studies of enzymatic mechanisms represent only part of my research interests. A number of other areas, especially the design of semi-synthetic enzymes, the molecular basis of aging and the chemical mechanisms of the immune response, have attracted my attention and are research problems that I would like to investigate in the future. It is my hope that the areas chosen for my research and the results yielded from it will advance chemical knowledge, and have applications in the fields of medicine and/or agriculture. Since my research is moving on to attack more fundamental and difficult problems that will require much of me in the way of attention and self-education, a Research Career Development Award given at this time would come at a critical juncture. It will allow me to fully concentrate on working at the bench myself and supervising the efforts of my coworkers, and also give the freedom to spend time in other laboratories to learn different techniques and perspectives which can be brought back to bear on new areas of inquiry. By agreement with the Chairman, I wig teach for one quarter each year. This teaching activity will keep me sufficiently involved in the flow of the Department, and will help maintain the profile necessary to interest graduate students who are seeking a research advisor. Thus, a Research Career Development Award would make a real difference for me by allowing maximum concentration on research, which is necessary in order to mature into a productive and established investigator.