MODELS FOR CYTOCHROME P-450 HYDROXYLASES

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This research is directed towards functional analogues of the enzyme family cytochromes P-450. These mixed-function oxygenases are involved in sterol biosynthesis and metabolism, in drug detoxification, and in bioactivation of xenobiotics to toxic and carcinogenic products. The present studies are intended to provide a molecular background for the mechanisms of oxygen activation and transfer, and of suicide inhibition during the function of the enzymes P-450. Novel metalloporphyrin compounds will by synthesized and examined as catalysts for the oxygenation of various organic substrates. Analogues of ,he intermediate stages in the P-450 reaction cycle will be isolated, characterized, and then reaction chemistry will be studied. This work will focus on the special role of the cysteine mercaptide ligand and of activators in the heterolytic reductive cleavage of dioxygen during the P-450 reaction cycle. Various electrochemical techniques with flavin mediators will be used to mimic the two critical single-electron transfer steps in the P-450 reaction sequence. Electrochemistry, kinetics measurements, synthetic organic and inorganic chemistry and a range of spectroscopic techniques (1H NMR, IR, Raman, MCD, Mossbauer, X-ray diffraction and EXAFS) will be used in this molecular biomimetic research. Ruthenium analogues of the iron atoms in heme centers will be prepared and studied in the context of P-450 chemistry.