Investigation of Nitric Oxide Synthase Structure, Function and Inhibition

点击翻译按钮获取中文摘要

Nitric oxide (NO) is an important endogenous messenger in a variety of physiological and pathophysiological processes. NO is synthesized by the three isoforms of nitric oxide synthase (NOS) that are encoded by different genes, neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). The dual role of NO in the body as a second messenger or cytotoxic agent shows the importance for tight regulation of the different NOS isoforms. Each subunit of NOS is composed of a reductase domain that contains the binding sites for NADPH, and two flavins as well as an oxygenase domain that contains the binding sites for heme, L-arginine and tetrahydrobiopterin. The two domains are linked by a calmodulin (CaM) binding domain that plays an important role in the activation of the enzyme. CaM is the primary protein mediator of the calcium cation that is also an important secondary messenger. CaM undergoes calcium-dependent conformational changes that allow it to bind and activate scores of target proteins including all three NOS isozymes. Two of the long-term goals of this research program are to: 1) understand the mechanism(s) of CaM binding and control for all three NOS isozymes; 2) study the selective ligand binding and inhibition of human NOS isozymes.