Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several types of compound exert their cytotoxicity by generating reactive oxygen species, notably the superoxide anion radical. These include quinoid and nitroaromatic compounds serving as redox cyclers, i.e. producing superoxide at the expense of NADPH and oxygen catalyzed by cellular reductases. In specialized cell-types employed in defense such as granulocytes, eosinophils and macrophages, myeloperoxidase, NADPH oxidase and nitric oxide synthase have been identified as major sources of reactive oxygen species in cell toxicity. These include hypochlorite, singlet oxygen, superoxide, nitric oxide and hydrogen peroxide. The interaction of superoxide and nitric oxide generates further oxidants such as peroxynitrite. Lumino-amplified chemiluminescence generated by Kupffer cells is partially sensitive to inhibitors of NO synthase. Superoxide dismutase has been found to catalyze a novel reaction, the reversible conversion of nitric oxide to the nitroxyl anion, the latter being viewed as another form of EDRF. In the defense against oxidative damage, there are enzymatic and nonenzymatic antioxidants. Regarding compounds used pharmacologically, we have been interested in ebselen, a seleno-organic compound exhibiting GSH peroxidase activity, which protects against reactive oxygen species generated, for example, at reoxygenation following a period of hypoxia. Further, we have studied lipoate and dihydrolipoate as antioxidant redox system and as singlet oxygen quencher, e.g. protecting against damage of deoxyguanosines in plasmid DNA generated by singlet oxygen.
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PMID:Role of reactive oxygen species in cell toxicity. 133 81

Luminol chemiluminescence in phorbolester-activated cultured rat liver Kupffer cells was strongly inhibited by the selenoorganic compound ebselen (IC50 = 2 mumol/L). Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one) also diminished reduction of ferricytochrome c (IC50 = 10 mumol/L), indicating a suppression of superoxide anion formation. Likewise, in lipopolysaccharide-pretreated Kupffer cells, ebselen proved to be a potent inhibitor of the conversion of oxyhemoglobin to methemoglobin (IC50 = 3 mumol/L) as a measure of nitric oxide formation. The sulfur-containing analog (2-phenyl-1,2-benzisothiazol-3[2H]one) and the ebselen derivative, methylselenobenzanilide, were inactive. These results indicate that ebselen is a potent inhibitor of NADPH oxidase in Kupffer cells, as has been reported for other macrophages and granulocytes. In addition, they suggest a novel characteristic of ebselen, namely very effective inhibition of nitric oxide synthase of macrophages. In line with its inhibitory effects on the release of reactive oxygen species by macrophages, complemented by its antioxidant properties, ebselen was potent in the prevention of reoxygenation injury of Kupffer cells (IC50 approximately 5 mumol/L).
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PMID:Inhibition of superoxide and nitric oxide release and protection from reoxygenation injury by Ebselen in rat Kupffer cells. 137 78

Brain nitric oxide synthase is a Ca2+/calmodulin-regulated enzyme which converts L-arginine into NO. Enzymatic activity of this enzyme essentially depends on NADPH and is stimulated by tetrahydrobiopterin (H4biopterin). We found that purified NO synthase contains enzyme-bound H4biopterin, explaining the enzymatic activity observed in the absence of added cofactor. Together with the finding that H4biopterin was effective at substoichiometrical concentrations, these results indicate that NO synthase essentially depends on H4biopterin as a cofactor which is recycled during enzymatic NO formation. We found that the purified enzyme also contains FAD, FMN and non-heme iron in equimolar amounts and exhibits striking activities, including a Ca2+/calmodulin-dependent NADPH oxidase activity, leading to the formation of hydrogen peroxide at suboptimal concentrations of L-arginine or H4biopterin.
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PMID:Brain nitric oxide synthase is a biopterin- and flavin-containing multi-functional oxido-reductase. 171 90

Phorbol 12-myristate 13-acetate-induced luminol chemiluminescence in rat Kupffer cells was doubled by the addition of L-arginine and significantly (up to 70%) inhibited by NG-nitro-L-arginine and NG-monomethyl-L-arginine, competitive inhibitors of L-arginine-dependent nitric oxide (NO) formation. The release of superoxide anion (O2-) by NADPH oxidase was neither affected by L-arginine nor by the inhibitors. Only very slight luminol chemiluminescence was detectable in lipopolysaccharide-pretreated Kupffer cells, a condition in which significant amounts of NO were formed but no O2-. In a cell-free system, significant luminol chemiluminescence only occurred when both authentic NO and the O2-/H2O2- generating system xanthine/xanthine oxidase were present. The results indicate that luminol chemiluminescence in phorbol-ester-activated Kupffer cells largely depends on L-arginine metabolism by NO synthase, requiring the concurrent formation of NO and O2-/H2O2.
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PMID:Contribution of nitric oxide synthase to luminol-dependent chemiluminescence generated by phorbol-ester-activated Kupffer cells. 171 62

A slow-growing mutant of Escherichia coli with greatly elevated nicotinamide adenine dinucleotide phosphate (reduced; NADPH) oxidase activity has been isolated. The oxidase activity of the wild-type organism, normally low at pH 7.5, was increased when the assay was performed at pH 6.0. Sucrose density gradients of sonic extracts of the mutant and wild-type strains revealed several peaks of NADPH oxidase activity at pH 6.0. The parent organism had a peak of activity of high molecular weight which was absent from the mutant. The mutant strain had an activator capable of increasing the activity of all wild-type density gradient peaks, especially the one of high molecular weight. The activator was either missing or masked in the wild type. Agar gel electrophoresis of the extracts uncovered a rapidly moving band from the wild type, missing from the mutant; the material in this band had weak NADPH-diaphorase activity and strongly inhibited the activity of the mutant NADPH oxidase. It was concluded that, in wild-type E. coli, NADPH oxidase activity is regulated by a proper balance of an activator and an inhibitor. The absence of the inhibitor, as in the mutant, or the inactivation of the inhibitor at acid pH levels, results in a high level of NADPH oxidase activity. The relation of high NADPH oxidase levels and subsequent decrease of the NADPH pool to the decrease in growth rate is considered.
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PMID:Escherichia coli mutant with elevated nicotinamide adenine dinucleotide phosphate (reduced) oxidase activity. 438 86

Oxidised low-density lipoprotein (LDL) produced by the action of arterial cells, including macrophages, has been implicated in atherosclerosis. We have investigated the effect of inhibitors of various cellular free-radical generating enzymes on macrophage-mediated LDL oxidation. Xanthine oxidase and nitric oxide synthase are not responsible for LDL modification by resident mouse peritoneal macrophages. Eicosatetraynoic acid, a lipoxygenase inhibitor, produced a dose-dependent irreversible inhibition of macrophage modification of LDL, but at concentrations rather close to those toxic to the cells. Diphenyl and diphenylene iodonium, NADPH oxidase and mitochondrial electron transport inhibitors, inhibited macrophage oxidation of LDL, at concentrations that were not obviously toxic. This suggests that NADPH oxidase, or some other flavin nucleotide-dependent process, may be involved in LDL oxidation by macrophages. Wortmannin and thiopropionic acid dilauryl ester did not inhibit LDL oxidation, suggesting that inhibition of NADPH oxidase may not be the means by which the iodonium compounds inhibit LDL oxidation. Macrophages from C3H/HeJ mice, which lack receptors for lipopolysaccharide, modified LDL normally, suggesting that the inadvertent priming of resident macrophages by traces of lipopolysaccharide bound to LDL was not involved in LDL oxidation.
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PMID:The effect of inhibitors of free radical generating-enzymes on low-density lipoprotein oxidation by macrophages. 751 Jan 29

Research over the past year has revealed several interesting advances in the biosynthesis of the superoxide anion and nitric oxide. Highlights include the demonstration that the G protein Rac 2 is required for NADPH oxidase activation, the finding that nitric oxide is a feedback inhibitor of nitric oxide synthase isoforms, and the discovery that the continuous catalytic activity of the immune/inflammatory nitric oxide synthase is due to strong calmodulin binding, which is independent of elevated calcium levels. Interferon-gamma primes neutrophils and macrophages for both O2- and nitric oxide synthesis. However, NADPH oxidase and immune/inflammatory nitric oxide synthase are differentially regulated such that their activities are not simultaneously induced.
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PMID:Assembly and regulation of NADPH oxidase and nitric oxide synthase. 751 23

Citrulline formation by Ca(2+)-calmodulin (CaM)-dependent nitric oxide synthase from bovine brain is inhibited reversibly by indazole, 5-nitro-, 6-nitro-, and 7-nitroindazole with IC50 values of 2.3 mM, 1.15 mM, 40 microM, and 2.5 microM, respectively. Inhibition of citrulline formation by 7-nitroindazole exhibited a Ki value of 0.16 microM and was competitive versus both arginine substrate and (6R)-5,6,7,8-tetrahydrobiopterin cofactor. The NADPH oxidase activity of bovine brain CaM-dependent nitric oxide synthase was inhibited by 7-nitroindazole with an IC50 value of 0.6 microM. Citrulline formation by the interferon-gamma/lipopolysaccharide-inducible nitric oxide synthase of murine macrophages (264.7 cell line) is inhibited reversibly by indazole, 5-nitro-, 6-nitro-, and 7-nitroindazole with IC50 values of 470, 240, 56, and 20 microM, respectively. Inhibition of citrulline formation by 7-nitroindazole exhibited a Ki value of 1.6 microM and was noncompetitive versus arginine substrate but competitive versus (6R)-5,6,7,8-tetrahydrobiopterin cofactor. None of the indazoles tested inhibited the cytochrome c reductase activity of either nitric oxide synthase isoform at concentrations up to 1000-fold higher than their IC50 values for inhibition of citrulline formation. These observations are consistent with the proposal that the indazoles exert their inhibitory actions by interaction with the heme-iron of nitric oxide synthase such that oxygen does not bind.
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PMID:The inhibition of the constitutive and inducible nitric oxide synthase isoforms by indazole agents. 751 13

The dynamics and mechanisms of extracellular release of hydrogen peroxide (H2O2) from bovine pulmonary artery endothelial cells (EC) subjected to anoxia, hypoxia, and hypoxia followed by reoxygenation were examined using various inhibitors of enzymatic systems in intact cells and by direct measurement of H2O2 production from isolated EC plasma membranes. Extracellular H2O2 was measured with a fluorometric assay. EC exposed to hypoxia (3% O2) and anoxia (0% O2) released less H2O2 (29.6 +/- 1.3% and 4.2 +/- 0.7%, respectively) compared with EC exposed to normoxia (20% O2). The extracellular release of H2O2 from EC previously exposed to hypoxia for 24 h increased immediately after reoxygenation (20% O2) to 272 +/- 48%, as compared with EC exposed continuously to normoxia (100% release). Inhibition of xanthine oxidase (XO) by allopurinol did not reduce the release of H2O2 from cells exposed to normoxia or hypoxia followed by reoxygenation. Furthermore, inhibitors of cyclooxygenase (indomethacin), phospholipase A2 (quinacrine and chlorpromazine), nitric oxide synthase (L-arginine analogs), the mitochondrial electron transport chain (rotenone and cyanide), and cytochrome P-450 (methoxypsoralen) had no or minimal effect on this release. On the other hand, inhibitors of protein kinase C (calphostin and staurosporine) and NADPH oxidase (diphenyliodonium) reduced the release of H2O2 from EC in a dose-dependent manner in both exposure groups. In separate experiments, plasma membranes isolated from EC were found to produce H2O2 in the presence of NADH or NADPH as electron donors. This was inhibited by diphenyliodonium but not by allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of hydrogen peroxide in response to hypoxia-reoxygenation: role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. 752 30

Aminoguanidine produces a time-dependent inactivation of the citrulline forming activity of all three nitric oxide synthase isoforms that is blocked by arginine. Aminoguanidine inactivates both the NADPH oxidase and citrulline forming activities of GH3 pituitary constitutive nitric oxide synthase (cNOS) but does not alter its cytochrome c reductase activity. GH3 pituitary cells contain an NOS isoform identical physically, kinetically, and immunologically to cerebellar neuronal NOS (Wolff and Datto, Biochemical J. (1992) 285, 201-206). The inactivation of GH3 cNOS NADPH oxidase activity, as measured without added tetrahydrobiopterin cofactor, is saturable, is inhibited by arginine, and follows pseudo-first-order kinetics with an inactivation rate constant of 0.25 min-1 and a Ki value of 0.83 mM aminoguanidine. The inactivation of the citrulline forming activity of GH3 cNOS by aminoguanidine was not saturable by aminoguanidine. Aminoguanidine, at concentrations in the millimolar range, inhibited the citrulline forming activity of endothelial cNOS by an apparently nonsaturable mechanism. Aminoguanidine inactivates the citrulline forming activity of murine macrophage iNOS. The inactivation is saturable and follows pseudo-first-order kinetics with an inactivation rate constant of 0.46 min-1 and a Ki value of 16 microM. The inactivation of the constitutive isoforms of nitric oxide synthase by aminoguanidine required the concurrent presence of Ca2+, calmodulin, NADPH, tetrahydrobiopterin, and oxygen in preincubations and was not reversed either by dilution or dialysis. These observations support the assertion that aminoguanidine is a mechanism-based inactivator of the nitric oxide synthase isoforms and exhibits marked specificity for the inactivation of the inducible isoform.
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PMID:Aminoguanidine is an isoform-selective, mechanism-based inactivator of nitric oxide synthase. 753 Sep 37


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