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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Purine hydroxylase (PH) from Clostridium purinolyticum contains a labile selenium cofactor and belongs to a class of enzymes known as the selenium-dependent molybdenum hydroxylases. The presence of approximately 1.1 mol of molybdenum, 0.87 mol of selenium, and 3.3 mol of iron per mol of PH was determined by atomic absorption spectroscopy. Enzyme preparations with lower than stoichiometric amounts of selenium exhibited correspondingly lower hydroxylase activities. Bound FAD, 1 mol per mol enzyme, was confirmed by UV-vis and fluorescence spectroscopy. CMP, released by acid hydrolysis, indicated the presence of a molybdopterin cytosine dinucleotide cofactor. The fully active PH utilized NADP(+) as an electron acceptor, and kinetic analysis revealed an optimal k(cat) of 412 s(-1) using hypoxanthine as the hydroxylase substrate. Xanthine, NAD(+), and NADPH had no significant effect on this reaction rate. A selenium-independent NADPH oxidase activity was exhibited by native PH. Electron paramagnetic resonance spectroscopy revealed the presence of a Mo(V) desulfo signal, FAD radical, and 2Fe-2S centers in hypoxanthine-reduced PH. No hyperfine coupling of selenium, using (77)Se isotope-enriched PH, was observed in any of the EPR active signals studied. The appearance of the desulfo signal suggests that the ligands of Mo in selenium-dependent molybdenum hydroxylases are different from the well-studied mammalian xanthine oxidoreductases (XOR) and aldehyde oxidoreductases (AOR) and suggests a unique role for Se in catalysis.
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PMID:Cofactor determination and spectroscopic characterization of the selenium-dependent purine hydroxylase from Clostridium purinolyticum. 1450 89

Reactive oxygen species (ROS) play an important but not yet fully defined role in the expression of inflammatory genes such as monocyte chemoattractant protein (MCP)-1. We used complementary molecular and biochemical approaches to explore the roles of specific ROS and their molecular linkage to inflammatory signaling in endothelial cells. Adenovirus-mediated expression of superoxide dismutase and catalase inhibited TNF-alpha-induced MCP-1 gene expression, suggesting important roles of superoxide (O(2)(-).) and H(2)O(2) in MCP-1 gene activation. In addition, the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one and the hydroxyl radical scavengers dimethylthiourea and dimethyl sulfoxide inhibited TNF-alpha-induced MCP-1 expression, suggesting important roles of iron and hydroxyl radicals in inflammatory signal activation. In contrast, scavenging of peroxynitrite with 5,10,15,20-tetrakis-(4-sulfonatophenyl)prophyrinato iron (III) chloride had no effect on TNF-alpha-induced MCP-1 expression. Inhibition of NADPH oxidase, the major oxidase responsible for O(2)(-). generation, with diphenylene iodonium suppressed TNF-alpha-induced MCP-1 mRNA accumulation. Rac1 is an upstream signaling molecule for the activation of NADPH oxidase and O(2)(-). generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF-alpha-induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-alpha-induced MCP-1 and NF-kappaB transcriptional activity. These data suggest that ROS such as superoxide and H(2)O(2) derived from Rac1-activated NADPH oxidase mediate TNF-alpha-induced MCP-1 expression in endothelial cells.
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PMID:Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase. 1457 80

This study was designed to measure the effects of iron supplementation on respiratory burst in iron-deficient anemia. The performance of neutrophils was evaluated by measuring the activity of NADPH oxidase in 18 patients with iron-deficient anemia before and after body iron stores are saturated. The activity of NADPH oxidase was significantly lower in pretreatment patients relative to controls (p<0.05). The activity increased after iron supplementation to levels that had no significant differences relative to controls.
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PMID:Activity of neutrophil NADPH oxidase in iron-deficient anemia. 1471 89

Nitric oxide (NO) has been found to inhibit the actions of the transmembrane metal reductase Fre1 in the yeast Saccharomyces cerevisiae. This membrane-spanning heme protein is homologous to the gp91(PHOX) protein of the NADPH oxidase enzyme complex and is responsible for reducing extracellular oxidized metals (i.e., ferric and cupric ions) before high-affinity uptake. Consistent with its role in metal metabolism, inhibition of Fre1 by NO also inhibited yeast growth in low-iron medium. Inhibition by NO was found to be O(2)-dependent and irreversible. Further examination of the chemistry responsible for activity loss shows that the generation of N(2)O(3) via NO-O(2) chemistry was responsible for the activity loss, possibly via nitrosation of the protein followed by loss of the heme prosthetic group.
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PMID:Inhibition of the yeast metal reductase heme protein fre1 by nitric oxide (NO): a model for inhibition of NADPH oxidase by NO. 1528 28

Solute carrier family 11a member 1 (Slc11a1; formerly natural resistance-associated macrophage protein 1) encodes a late endosomal/lysosomal protein/divalent cation transporter, which regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 exerts pleiotropic effects on gene regulation and function, including generation of nitric oxide (NO) via inducible NO synthase (iNOS; encoded by Nos2A) and of reactive oxygen intermediates (ROI) via the phagocyte oxidase complex. As NO and ROI have potent antimicrobial activity in macrophages, it was assumed that their activities would contribute to Slc11a1-regulated innate resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani. By intercrossing mice with gene disruptions at Nos2A and Cybb (encoding gp91phox, the heavy chain subunit of cytochrome b-245 and an essential component of phagocyte NADPH oxidase) onto equivalent Slc11a1 wild-type and mutant genetic backgrounds, we demonstrate that neither iNOS nor gp91phox activity is required for Slc11a1-mediated innate resistance to either infection. Functional gp91phox and iNOS are required to control S. enterica serovar Typhimurium in non-Slc11a1-regulated phases of infection. For L. donovani, an organ-specific requirement for iNOS to clear parasites from the spleen was observed at 50 days post-infection, but neither iNOS nor gp91phox influenced late-phase infection in the liver. This contrasted with Leishmania major infection, which caused rapid lesion growth and death in iNOS knockout mice and some exacerbation of disease with gp91phox deficiency. This highlights the adaptive differences in tissue and cellular tropisms between L. donovani and L. major and the different genes and mechanisms that regulate visceral versus cutaneous forms of the disease.
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PMID:Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity. 1560 66

Iron deficiency is associated with multiple health problems, including the cardiovascular system. However, the mechanism of action of iron-deficiency-induced cardiovascular damage is unclear. The aim of the present study was to examine the effect of dietary iron deficiency on cardiac ultrastructure, mitochondrial cytochrome c release, NOS (nitric oxide synthase) and several stress-related protein molecules, including protein nitrotyrosine, the p47phox subunit of NADPH oxidase, caveolin-1 and RhoA. Male weanling rats were fed with either control or iron-deficient diets for 12 weeks. Cardiac ultrastructure was examined by transmission electron microscopy. Western blot analysis was used to evaluate cytochrome c, endothelial and inducible NOS, NADPH oxidase, caveolin-1 and RhoA. Protein nitrotyrosine formation was measured by ELISA. Rats fed an iron-deficient diet exhibited increased heart weight and size compared with the control group. Heart width, length and ventricular free wall thickness were similar between the two groups. However, the left ventricular dimension and chamber volume were significantly enhanced in the iron-deficient group compared with controls. Ultrastructural examination revealed mitochondrial swelling and abnormal sarcomere structure in iron-deficient ventricular tissues. Cytochrome c release was significantly enhanced in iron-deficient rats. Protein expression of eNOS (endothelial NOS) and iNOS (inducible NOS), and protein nitrotyrosine formation were significantly elevated in cardiac tissue or mitochondrial extraction from the iron-deficient group. Significantly up-regulated NADPH oxidase, caveolin-1 and RhoA expression were also detected in ventricular tissue of the iron-deficient group. Taken together, these results suggest that dietary iron deficiency may have induced cardiac hypertrophy characterized by aberrant mitochondrial and irregular sarcomere organization, which was accompanied by increased reactive nitrogen species and RhoA expression.
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PMID:Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration. 1587 45

Although blood cell-endothelial cell adhesion and oxidative stress have been implicated in the pathogenesis of sickle cell disease (SCD), the nature of the linkage between these vascular responses in SCD remains unclear. The objective of this study was to determine whether superoxide derived from endothelial cell-associated NADPH oxidase mediates the leukocyte-endothelial (L/E) and platelet-endothelial cell (P/E) adhesion that is observed in the cerebral microvasculature of sickle cell transgenic (betaS) mice. Intravital fluorescence microscopy was used to monitor L/E and P/E adhesion in brain postcapillary venules of wild-type (WT), SOD1 transgenic (SOD1-TgN), and gp91phox (NADPH oxidase)-deficient mice that were transplanted with bone marrow from betaS mice. Hypoxia/reoxygenation (H/R) yielded intense P/E and L/E adhesion responses in cerebral venules of betaS/WT chimeras that were significantly attenuated in both betaS/SOD1-TgN, and betaS/gp91phox-/- chimeras. Pretreatment of betaS/WT chimeras with the iron-chelator desferroxamine blunted the blood cell-endothelial cell adhesion responses to H/R, whereas pretreatment with the xanthine oxidase inhibitor allopurinol had no effect. These findings suggest that superoxide derived from endothelial cell NADPH-oxidase and catalytically active iron contribute to the proinflammatory and prothrombogenic responses associated with sickle cell disease.
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PMID:Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice. 1592 6

Alveolar macrophages play a critical role in silica-induced lung fibrosis, and apoptotic mechanisms have been implicated in silica-induced pathogenesis. Here, employing a model of murine macrophages (J774 cells), it is shown that serum-coated alpha-quartz silica particles cause lysosomal rupture and apoptosis following endocytotic uptake. The loss of lysosomal integrity involves intralysosomal iron-catalyzed peroxidative damage to lysosomal membranes. Thus, lysosomal damage is most pronounced in cells exposed to silica particles with high amounts of surface-bound iron, whereas silica particles previously treated with the iron chelator desferrioxamine only induce modest rupture. Furthermore, inhibition of intralysosomal Fenton type chemistry, either by pre-treatment with desferrioxamine complexed to starch--an iron chelator targeted to the lysosomal compartment--or by concomitant treatment with diphenylene iodonium--a potent inhibitor of NADPH oxidase --both prevent silica-induced lysosomal leakage and ensuing apoptotic cell death. This study also demonstrates that silica-induced lysosomal rupture is a very early apoptotic event, preceding activation of caspases, disruption of transmembrane mitochondrial potential and DNA fragmentation. Indeed, these later apoptotic events appear to be directly correlated to the magnitude of lysosomal leakage, and are not observed in cells treated with high molecular weight desferrioxamine or diphenylene iodonium.
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PMID:Iron-dependent lysosomal destabilization initiates silica-induced apoptosis in murine macrophages. 1594 5

Rat hepatoma HTC cells are intrinsically resistant to various apoptosis-inducing agents. Strategies to induce death in hepatoma cells are needed and the present experimental study was aimed to investigate the sensitivity of HTC cells to TNF and to clarify the mechanisms of action of this cytokine. Cells were treated with TNF and death mechanisms characterized employing an integration of morphological and biochemical techniques. HTC cells, sensitized to TNF toxicity with cycloheximide, died in a caspase-independent apoptosis-like manner. Although we found no evidence for a direct involvement of lysosomal cathepsins, bafilomycin A1 and ammonium chloride significantly attenuated TNF toxicity. Also desferrioxamine mesylate, an iron chelator, partly protected the cells from TNF, while a complete protection was afforded by combining ammonium chloride and iron chelator. Moreover, HTC were protected from TNF also by lipophylic antioxidants and diphenylene iodonium chloride, a NADPH oxidase inhibitor. These data depict a novel mechanism of TNF-mediated cytotoxicity in HTC cells, in which the endo-lysosomal compartment, NADPH oxidase and an iron-mediated pro-oxidant status contribute in determining a caspase-independent, apoptosis-like cell death.
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PMID:Intracellular free iron and acidic pathways mediate TNF-induced death of rat hepatoma cells. 1613 68

Ferritin is a major intracellular iron storage protein and also functions as a cytoprotectant by sequestering iron to minimize the formation of reactive oxygen species. Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis, is an obligate intracellular bacterium that colonizes neutrophils. We have previously reported that human promyelocytic HL-60 cells infected with A. phagocytophilum demonstrate increased transcription of ferritin heavy chain and also that the bacterium stimulates neutrophil NADPH oxidase assembly and degranulation during the initial hours of infection (J. A. Carlyon, W. T. Chan, J. Galan, D. Roos, and E. Fikrig, J. Immunol. 169:7009-7018, 2002, and J. A. Carlyon, D. Abdel-Latif, M. Pypaert, P. Lacy, and E. Fikrig, Infect. Immun. 72:4772-4783, 2004). In this study, we assessed ferritin mRNA and protein levels during A. phagocytophilum infection in vitro using HL-60 cells and neutrophils and in vivo using neutrophils from infected mice. The addition of A. phagocytophilum, as well as Escherichia coli and serum-opsonized zymosan, to neutrophils results in a pronounced increase in ferritin light-chain transcription and a concomitant rise in ferritin protein levels. Neutrophils from A. phagocytophilum-infected mice demonstrate elevated ferritin heavy-chain mRNA expression, a phenomenon consistent with infections by intracellular pathogens. Notably, ferritin protein levels of infected HL-60 cells were markedly diminished in a dose- and time-dependent manner. These studies provide insight into the effects A. phagocytophilum has on the ferritin levels of its host cell.
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PMID:Effects of Anaplasma phagocytophilum on host cell ferritin mRNA and protein levels. 1623 67


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