Nitric oxide synthase structure and electron transfer

The nitric oxide synthases (NOS), although unrelated to the cytochromes P45 0 in terms of sequence, exhibit spectroscopic and catalytic properties stro ngly reminiscent of those of the P450 system. One important difference is t he requirement of the NOS enzymes for tetrahydrobiopterin. The biopterin co factor is shown by chemical studies to bind close to pyrrole ring D of the prosthetic heme group, a position confirmed recently for inducible NOS and endothelial NOS by crystal structures. The only plausible role so far for t he tetrahydrobiopterin is as a transient electron donor for the activation of molecular oxygen. NADPH-derived electrons are provided to the heme by th e NOS flavin domain, but the biopterin may be required to provide an electr on at a faster rate than that supported by the flavin groups. Chimeras in w hich the reductase domains of the isoforms have been exchanged indicate tha t the overall rate of catalytic turnover is directly governed by the abilit y of the flavin domain to deliver electrons. Electron transfer from the fla vin to the heme domain, and within the flavin end heme domains, is thus a c ritical determinant of the catalytic turnover of NOS.