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J Biol Chem, Vol. 273, Issue 22, 13502-13508, May 29, 1998

Reaction of Neuronal Nitric-oxide Synthase with Oxygen at Low Temperature
EVIDENCE FOR REDUCTIVE ACTIVATION OF THE OXY-FERROUS COMPLEX BY TETRAHYDROBIOPTERIN

Nicole Bec, Antonius C. F. Gorren^§, Christof Voelker^§, Bernd Mayer^§, and Reinhard Lange

From the  Institut National de la Santé et de la Recherche Scientifique, U 128, Institut Fédératif de Recherche 24, 34293 Montpellier, France and the ^§ Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität, 8010 Graz, Austria

The reaction of reduced NO synthase (NOS) with molecular oxygen was studied at 30 °C. In the absence of substrate, the complex formed between ferrous NOS and O₂ was sufficiently long lived for a precise spectroscopic characterization. This complex displayed similar spectral characteristics as the oxyferrous complex of cytochrome P450 (_max = 416.5 nm). It then decomposed to the ferric state. The oxidation of the flavin components was much slower and could be observed only at temperatures higher than 20 °C. In the presence of substrate (L-arginine), another, 12-nm blue-shifted, intermediate spectrum was formed. The breakdown of the latter species resulted in the production of N-hydroxy-L-arginine in a stoichiometry of maximally 52% per NOS heme. This product formation took place also in the absence of the reductase domain of NOS. Both formation of the blue-shifted intermediate and of N-hydroxy-L-arginine required the presence of tetrahydrobiopterin (BH₄). We propose that the blue-shifted intermediate is the result of reductive activation of the oxygenated complex, and the electron is provided by BH₄. These observations suggest that the reduction of the oxyferroheme complex may be the main function of BH₄ in NOS catalysis.

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