We seek a precise understanding of biological oxidase and oxygenase mechanism, the interaction of metal centers with terminal oxidants, particularly the reductive cleavage of oxygen and nitrogen compounds, and the related concomitant electron transfer processes. The primary system in these investigations is the cytochrome P-450 mixed function oxidase, which plays a central and crucial role in mammalian, plant, and microbe metabolism. Primary reactions catalyzed by P-450 monoxygenases of immediate relevance include the detoxification of ingested environmental toxins and pollutants, carcinogen activation and deactivation carried out in the human liver, and steroid hormone synthesis in adrenal and other tissues. All of these monoxygenation reactions reduce atmospheric O2 producing water, and a monoxygenated substrate. Central questions as to the mechanisms of these important reactions are the mode of regulation and control of biological activity, the precise chemistry of carbon substrate and oxygen activation related to the catalytic event, the mechanistic details surrounding concerted inter- and intra-protein electron transfer, and the role of multi-enzyme complexes and conformer equilibria in catalytic oxygenation and redox movement. Systems to be utilized include the hepatic microsomal P-450 hydroxylase active in drug metabolism, the camphor monoxygenase, and the adrenal side chain cleavage and 11-Beta mixed function oxidases on the aldosterone pathway. Detailed knowledge is also sought with regard to the oxidative mechanisms of the redox active anti-tumor drugs mitomycin C, bleomycin, and adriamycin which display many similarities in metalloenzyme function. Through these efforts, the fundamental and current ideas, techniques, methods, and theories of chemistry, biology, and physics will be brought to bear in concerted fashion on some of the most important problems of modern molecular biochemistry, providing insight into the inner workings of these processes and aiding therapeutic prescription through detailed knowledge of regulation.
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