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Oxidative Denitrification Of Nω-hydroxy-l-arginine By The Superoxide Radical Anion

Steven A. EVERETT, Madeleine F. DENNIS, Kantilal B. PATEL, Michael R. L. STRATFORD, Peter WARDMAN

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The superoxide radical anion (O2-•) produced during the catalytic activity of nitric oxide synthase (NOS) and cytochrome P-450 has been implicated in the oxidative denitrification of hydroxyguanidines (> C = NOH). The reactivity of the radiolytically generated O2-• radical with Nω-hydroxy-l-arginine (NHA) is pH dependent and appears to parallel the prototropic equilibrium of the hydroxyguanidino group (> C = NOH ⇌ > C = NO- + H+; pK = 8). The Nω-hydroxyguanidino group is more reactive towards O2-• when deprotonated but exhibits negligible reactivity when protonated. Based on a model, the rate constant for the reaction of the O2-• with NHA was estimated as k (O2-•+ > C = NO-) ≈ 200–500 M-1·s-1, which is probably too low to compete with O2-• reactions with NO• or superoxide dismutase, which occur many orders of magnitude faster. The oxidative elimination of NO from NHA by O2-• was not accompanied by the formation of l-citrulline. Since only 21% of NHA will exist in the deprotonated > C = NO- form at physiological pH, it is unlikely that oxidative denitrification of NHA by cytochrome P-450 or NOS-derived O2-• radicals will prove a major free-radical pathway to NO• and l-citrulline.