NITRIC OXIDE INHIBITION OF TARGET ENZYMES

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Over the last several years nitric oxide (NO) has emerged as an important mediator in several key physiological processes. In general, when synthesized for blood vessel homeostasis, neuronal communication, and immune system function the levels of NO are tightly controlled. In addition, sustained or elevated synthesis of NO can be deleterious and may be important in the etiology of endotoxic shock, inflammation-related tissue damage, neuronal pathology and N-nitrosamine-induced carcinogenesis. Furthermore, NO can cause mutations in human cells and bacteria via deamination reactions with DNA. The inducible NOS has been implicated as the source of the sustained NO formation. Receptor mediated NO formation by the constitutive enzyme in response to the excitatory amino acid glutamate has now been exciting but has opened the door to some important questions regarding the toxicity of this reactive molecule. The overall long-term goal for this project is a thorough characterization of the reactivity of NO under biological conditions. An understanding of this reactivity is integral to the disease states brought about by high and sustained levels of NO synthesis. The specific aims of this project are as follows: The aims of this reactions, (2) characterize the neutrophil NOS, (3) study peroxidase and myeloperoxidase catalyzed reactions with NO and nitrosation reactions, (4) study non- target cell defense systems against NO, (5) provide key reagents to other projects including: cDNA for the murine macrophage NO synthase (NOS) for the collaborative liver expression experiments, N-alkyl-L-arginine derivatives as inhibitors for the NOS, and polyclonal antibodies against the inducible NOS.