MEDI 224 |
| Nitric oxide synthases (NOS) are cytochrome P450-like hemoprotein enzymes that catalyze the conversion of L-arginine to citrulline and NO. NO is a gaseous signaling molecule that is involved in a variety of physiological processes, including neurotransmission and penile erection. NOS was used as model to probe how drug-derived reactive metabolites cause NOS dysfunction and toxicity. We found that certain guanidine-based drugs are metabolized by NOS to reactive intermediates that cause the inactivation, covalent alteration, and enhanced proteasomal degradation of NOS. Moreover, the hsp90- and hsp70- based chaperones were found to play a critical role in directing the selective culling or repair of the inactivated NOS. We present a model that describes how chaperones recognize covalently altered proteins and direct NOS protein quality control. These studies indicate that drug-mediated stabilization and destabilization of proteins is an important consideration in the pharmacological and toxicological aspects of drug development. Supported in part by NIH GM77430 and DA22354 |
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Drug Safety
9:00 AM-12:00 PM, Tuesday, August 21, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |