CYTOCHROMES-P450 .3. NEURONAL NITRIC-OXIDE SYNTHASE, A MODULAR ENZYMEFORMED BY CONVERGENT EVOLUTION - STRUCTURE STUDIES OF A CYSTEINE THIOLATE-LIGANDED HEME PROTEIN THAT HYDROXYLATES L-ARGININE TO PRODUCE NO-CENTER-DOT AS A CELLULAR SIGNAL

The nitric oxide synthases (NOS-I, neuronal, NOS-II, inducible, and NO S-III, endothelial) are the most recent additions to the large number of heme proteins that contain cysteine thiolate-liganded protoporphyri n IX heme prosthetic groups. This group of oxygenating enzymes also in cludes one of the largest gene families, that of the cytochromes P450, which have been demonstrated to be involved in the hydroxylation of a variety of substrates, including endogenous compounds (steroids, fatt y acids, and prostaglandins) and exogenous compounds (therapeutic drug s, environmental toxicants, and carcinogens). The substrates for cytoc hromes P450 are universally hydrophobic while the physiological substr ate for the nitric oxide synthases is the amino acid. L-arginine, a hy drophilic compound. This review will discuss the approaches being used to study the structure and mechanism of neuronal nitric oxide synthas e in the context of its known prosthetic groups and regulation by Ca2-calmodulin and/or tetrahydrobiopterin (BH4).