Abstract
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.
Footnotes
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Supported by National Institutes of Health Grant ES08365. Y.O. is an Established Investigator of the American Heart Association. E.R.L. is a trainee under the Pharmacological Sciences Training Program GM07767 from the National Institutes of Health.
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DOI: 10.1124/jpet.102.035055
- Abbreviations:
- NOS
- nitric oxide synthase
- nNOS
- neuronal NOS
- iNOS
- inducible NOS
- eNOS
- endothelial NOS
- MG132
- carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal
- P450
- cytochrome P450
- apo-NOS
- heme-deficient form of NOS
- Received September 13, 2002.
- Accepted October 21, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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