This is a proposal that describes studies that focus primarily on the proteins Nitric Oxide Synthase (NOS) and Cytochrome c Oxidase (CCO), and with smaller efforts being devoted to Heme Oxygenase (HO) and the Fe-bleomycin complex. The theme of this work is to determine the properties of catalytic intermediates involving oxygen activation and utilization and all four subjects of this proposal produce such intermediates. Raman and optical spectroscopies will be used in these studies. NOS is the enzyme that generates nitric oxide from arginine and this proposal involves expanding significant preliminary studies in order to mechanistically characterize how the enzyme generates and controls NO. NO is, of course and important physiological molecule, playing roles in neurotransmission, vasodilation and cytotoxicity. CCO is the terminal enzyme in the electron transfer chain and it plays a dual role, reducing molecular oxygen to water and translocating protons across the inner mitochondrial membrane. The goal for this enzyme is to continue the body of significant preliminary work on this enzyme that has been produced in the PI's laboratory in order to determine structural features of the intermediates in the catalytic cycle for the mammalian enzyme and to determine the kinetics associated with these intermediates. HO is the rate-limiting enzyme of the microsomal heme degradation pathway and its role is to bind Iron-protoporphyrinIX and convert it to biliverdin- IX(alpha). Bleomycin is a glycopeptide antibiotic that exhibits antitumor activity towards neoplasms. The mechanism of this drugs effect is unknown, but evidence suggest that it involves activated oxygen intermediates.
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