The Chemistry and Biology of Nitroxyl (HNO): A Chemically Unique Species with Novel and Important Biological Activity

Fukuto, Jon M.; Dutton, Andrew S.; Houk, K. N.

doi:10.1002/cbic.200400271

Cited by 98 publications

(98 citation statements)

References 81 publications

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“…Explanations of this phenomena include the uncoupled reaction (10 -12), the formation of nitroxyl (13)(14)(15)(16), which is a further reduced form of NO, and the complexity of other subsequent reactions caused by highly reactive oxygen/nitrogen species (17,18). For the uncoupled reactions, many independent research groups use the EPR spin trap technique to monitor O 2 .…”

Section: Nitric-oxide Synthases (Nos)mentioning

confidence: 99%

Oxygen Metabolism by Neuronal Nitric-oxide Synthase

Gao

Panda

Roman

et al. 2007

Journal of Biological Chemistry

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Nitric-oxide synthases (NOS) catalyze nitric oxide (NO) formation from the amino acid L-arginine. NOS is known to catalyze more than one reaction: the NO-producing reaction is considered to be the coupled reaction, and the uncoupled reactions are those that produce reactive (reduced) oxygen species (ROS), such as superoxide anion (O 2 . ) and/or hydrogen peroxide (H 2 O 2 ). As an oxygenase, NOS has been known for more than two decades, yet there is no complete description of oxygen stoichiometry. The present paper is focused on oxygen stoichiometry and the effects of cofactor binding on the neuronal isoform (nNOS) on oxygen uptake and product formation. Products of the uncoupled reactions are analyzed using diacetyldeuteroheme-substituted horseradish peroxidase as a trapping agent for both O 2 . and H 2 O 2 . The addition of calmodulin not only stimulated the oxygen uptake rate but also changed the product of the uncoupled reaction, supporting the possibility of two different sites for electron leakage to molecular oxygen. Quantitative analysis of the uncoupled (substrate-free) reaction revealed a stoichiometry close to the theoretical value, and adding L-arginine not only initiates the coupled reaction, but also inhibits oxygen uptake. The presence of tetrahydrobiopterin affects oxygen metabolism by lowering the apparent K m value of nNOS for oxygen in the uncoupled reaction.Nitric-oxide synthases (NOS) 2 constitute a family of modular redox enzymes. Structurally, all NOS isoforms have an N-terminal heme or oxygenase domain and a C-terminal flavin or reductase domain connected by a calmodulin binding region (1, 2). These enzymes catalyze the conversion of L-arginine to nitric oxide (NO) and L-citrulline through a series of two monooxygenase reactions (3, 4). Electron flow commences upon the oxidation of NADPH, and electrons pass through FAD to FMN. Upon binding of Ca 2ϩ /calmodulin, electrons are passed from the reductase domain to the heme domain where NO is formed. NO plays an important role in both physiological and pathological processes (5-8). Neuronal NOS is a tissuespecific NOS isoform expressed constitutively in neuronal cells of mammals, including humans. Influx of calcium into the cell is necessary for calmodulin to activate nNOS (2, 5).To form NO, oxygen must bind to the heme of NOS, where it is subsequently activated and split; one atom of oxygen is inserted into the substrate and one combines with two protons to form H 2 O. This reaction is said to be "coupled" when all the electrons from NADPH are utilized in the formation of monooxygenated product and H 2 O. In an "uncoupled" reaction, electrons leak to O 2 , producing superoxide anion and other reactive oxygen species (ROS). Fully coupled NO production (3, 4, 9) was proposed as the following reaction.This reaction is a two-step monooxygenation reaction that involves N -hydroxy-L-arginine (NOHA) as a tightly bound intermediate. First step of the reaction is as follows.The second step of the reaction is shown as Reaction 3.When NOS is fully cou...

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Section: Nitric-oxide Synthases (Nos)mentioning

confidence: 99%

Oxygen Metabolism by Neuronal Nitric-oxide Synthase

Gao

Panda

Roman

et al. 2007

Journal of Biological Chemistry

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“…In vitro studies reveal that nitroxyl can nitrosate heme proteins and convert biological thiols into the corresponding sulfinamides [4][5][6]. Nitroxyl can also be converted into other reactive nitrogen species under simulated physiological conditions [7,8], thus raising the question whether nitroxyl itself or some downstream decomposition product produces the observed biological effects.…”

Section: Introductionmentioning

confidence: 97%

Physical and structural properties of [Cu(BOT1)Cl]Cl, a fluorescent imaging probe for HNO

Royzen

Wilson

Lippard

2013

Journal of Inorganic Biochemistry

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“…HNO is an unstable weak acid (pK a ¼ 11.4) (16,17), which readily dimerizes to yield N 2 O (16), and like NO displays both prooxidative and antioxidative effects (18)(19)(20)(21)(22)(23)(24)(25). Hence, the ability of HXs to serve as HNO-donors and/or NO-donors under oxidizing environments is involved in both the beneficial and injurious activities.…”

Section: Introductionmentioning

confidence: 98%