title: The activation of metabolites of nitric oxide synthase by metals is both redox and oxygen dependent: a new feature of nitrogen oxide signaling.
abstract: Nitrite (NO(2)-), N (G)-hydroxy-L-arginine (NOHA), and hydroxylamine (NH(2)OH) are products of nitric oxide synthase (NOS) activity and can also be formed by secondary reactions of nitric oxide (NO). These compounds are commonly considered to be rather stable and as such to be dosimeters of NO biosynthesis. However, each can be converted via metal-catalyzed reactions into either NO or other reactive nitrogen oxide species (RNOS), such as nitrogen dioxide (NO(2)) and nitroxyl (HNO), which have biologic activities distinct from those of the parent molecules. Consequently, certain aspects of tissue regulation controlled by RNOS may be dictated to a significant extent by metal-dependent reactions, thereby offering unique advantages for cellular and tissue regulation. For instance, because many metal-catalyzed reactions depend on the redox and oxygen status of the cellular environment, such reactions could serve as redox indicators. Formation of RNOS by metal-mediated pathways would confine the chemistry of these species to specific cellular sites. Additionally, such mechanisms would be independent both of NO and NOS, thus increasing the lifetime of RNOS that react with NO. Thus metal-mediated conversion of nitrite, NOHA, and NH(2)OH into biologically active agents may provide a unique signaling mechanism. In this review, we discuss the biochemistry of such reactions in the context of their pharmacologic and biologic implications.
authors.affiliation: Tumor Biology Section, Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Donzelli
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Switzer
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Thomas
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Michael Graham
authors.initials: MG
authors.lastname: Espey
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.forename: S Bruce
authors.initials: SB
authors.lastname: King
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lazzarino
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Miranda
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
mesh_terms: D001120:Arginine / Q000378:metabolism; D005544:Forecasting; D006898:Hydroxylamines / Q000378:metabolism; D008670:Metals / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000737:chemistry*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009589:Nitrogen Oxides / Q000737:chemistry*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: D006898:Hydroxylamines; D008670:Metals; D009573:Nitrites; D009589:Nitrogen Oxides; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C039900:nitroxyl; D010100:Oxygen