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Enzyme Ingenuity in Biological Oxidations: a Trail Leading to Cytochrome P450

Those unfamiliar with basic research in biochemistry and related fields may assume that important discoveries are the result of brilliant ideas that are single mindedly pursued until, many years later, the answer is obtained, perhaps along with important biomedical applications. The progress of science is almost always more haphazard, as ambitious young scientists are influenced by their teachers, by the cooperative or competitive work of others, the availability of new techniques, and chance findings that may lead to different goals. Sixty years ago as an undergraduate at the University of Colorado, I took my first biochemistry course in the Chemistry Department taught by Professor Reuben Gustavson and had the good fortune to be invited by him to join his small research group studying steroid hormones. I had a tremendous amount to learn but was fascinated from then on with research and the possibility of making new discoveries. In these reflections the influence of my mentors/teachers, whom I much admired for their personal qualities and achievements, is acknowledged. Although my research over the years has taken many unexpected turns, a common thread has been an interest in biological oxidations, particularly those not readily explainable according to the predictions of organic chemistry. This curiosity has led to fundamental studies on the properties and mechanism of action of cytochrome P450, now often described as the most versatile biological catalyst known. Although this was not my original goal, the mammalian isoforms of this enzyme have turned out to be of biomedical importance because of their central involvement in the metabolism of steroids, drugs, and chemical carcinogens.