The biochemistry of carbon radicals has received relatively little attention despite the close biological association of carbon and oxygen radicals and the intense current interest in oxygen radical pathology. The focus of this proposal on carbon radicals reflects, in addition, their unique value as mechanistic probes. The proposed work builds on key advances made during the past period of support, particularly (a) the formulation of a rationale for the fact that radicals are produced by peroxidases but not monooxygenases, (b) the finding that protein radicals support cooxidation reactions, and (c) the development of improved spin trapping technology. The first goal is to elucidate the mechanisms of peroxidases and to determine the validity of the proposal that diffusible radical generation results from reaction with the heme edge rather than the activated oxygen. The second goal is to explore further the relationship between substrate structure and the production of diffusible carbon radicals by cytochrome P-450. The third goal is to continue the development of new spin traps and their use in studies of the physiological incidence of carbon radicals. The fourth goal is to explore the biological fates of carbon radicals, particularly their oxidation to cations and their reactions with unsaturated targets. The final goal is to elucidate the mechanisms involved in the migration of a radical center from one protein residue to another and the role of tyrosines in the oxidative binding of proteins to drugs and DNA. The collective intent of these studies is to advance our understanding of the biochemistry of carbon radicals and to clarify their toxicological potential.
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