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PERSPECTIVES IN PHARMACOLOGY

Proteolytic Degradation of Nitric Oxide Synthase: Effect of Inhibitors and Role of hsp90-Based Chaperones

From the Department of Pharmacology, the University of Michigan Medical School, Ann Arbor, Michigan

Nitric oxide synthase (NOS) is a highly regulated enzyme that produces nitric oxide, a critical messenger in many physiological processes. In this perspective, we explore the role of proteolytic degradation of NOS, in particular the inducible and neuronal isoforms of NOS, as a mechanism of regulation of the enzyme. The ubiquitin-proteasome and calpain pathways are the major proteolytic systems identified to date that are responsible for this regulated degradation. The degradation of NOS is affected by diverse agents, including glucocorticoids, caveolin, neurotoxic compounds, and certain NOS inhibitors. Some irreversible inactivators of NOS enhance the proteolytic degradation of the enzyme, and this property may be of great importance in understanding the biological effects of these inhibitors, some of which are being developed for clinical use. Analogies with the regulated degradation of liver microsomal cytochromes P450, which are related to NOS, provide a framework for understanding these processes. Finally, a new perspective on the regulation of NOS by hsp90-based chaperones is presented that involves facilitated heme insertion into the enzyme.

Address correspondence to: Yoichi Osawa, Department of Pharmacology, The University of Michigan Medical School, Medical Science Research Building III, Ann Arbor, Michigan. E-mail: osawa{at}umich.edu

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