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)

It has been reported that respiratory bursts with N-formylmethionylleucylphenylalanine, A23187, phorbol ester and fatty acids are switched off and on by modulating the net charges of plasma membranes in guinea-pig neutrophils (Miyahara, M. et al. (1987), Biochim. Biophys. Acta, 929, 253-262). In the present study, this was further extended in cells treated with protein kinase C inhibitors which completely suppressed the phorbol ester-dependent respiratory burst. This suggested that the initiation of the respiratory burst, which is generally accepted as linked to protein kinase C activation, might also be implicated in the net charge changes of plasma membranes. The above results were also supported by data obtained with a cell-free system reconstituted with plasma membranes and cytosolic fractions from unstimulated neutrophils, guanosine 5'-[gamma-thio]triphosphate and NADPH. Arachidonate stimulated NADPH oxidase activity accompanied by a marked phosphorylation of membrane proteins. The phosphorylation was sensitive to H-7, but it did not appear to be essential for the respiratory burst, because the oxidase activation was insensitive to H-7. Pretreating the plasma membranes with positively charged cetylamine inhibited the oxidase activation by arachidonate. These results suggest that a charge-dependent process, which does not use protein kinase C, may play an important role in the reaction leading to NADPH oxidase activation, and this may be related to the interaction of plasma membranes with the cytosolic activation factor.
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PMID:Charge-dependent regulation of NADPH oxidase activities in intact and subcellular systems of polymorphonuclear leukocytes. 340 44

Both cis and trans unsaturated fatty acids and sodium dodecyl sulfate activated NADPH oxidase in plasma membranes of human neutrophils in the presence of neutrophil cytosol. In contrast, 5,8,11,14-icosatetraynoic acid, saturated fatty acids, esters, peroxides and 4 beta-phorbol 12-myristate 13-acetate, a potent activator of protein kinase C, were inactive. 5,8,11,14-icosatetraynoic acid inhibited superoxide formation elicited by fatty acids. Guanosine 5'[gamma-thio]triphosphate (GTP[gamma S]), a potent activator of guanine-nucleotide-binding proteins (N-proteins) enhanced superoxide formation elicited by fatty acids up to fourfold, supporting our previous suggestion that NADPH oxidase is regulated by an N-protein [Seifert, R. et al. (1986) FEBS Lett. 205, 161-165]. Cytosols from various tissues, soybean lipoxygenase and protein kinase C, purified from chicken stomach, did not substitute neutrophil cytosol. The activity of neutrophil cytosol was destroyed by heating at 95 degrees C. Superoxide formation was not affected by the inhibitor of protein kinase C 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). Removal of cytosolic ATP by preincubation with hexokinase and glucose, dialysis of neutrophil cytosol or chelation of calcium with EGTA did not abolish the stimulatory effect of arachidonic acid and GTP[gamma S]. Thus, the cytosolic cofactor appears to be a neutrophil-specific and heat-labile protein, which is neither a lipoxygenase nor protein kinase C.
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PMID:Fatty-acid-induced activation of NADPH oxidase in plasma membranes of human neutrophils depends on neutrophil cytosol and is potentiated by stable guanine nucleotides. 354 90

The superoxide-generating enzyme of human neutrophils, NADPH oxidase, is converted from an inactive to an active form upon stimulation of the neutrophil. This activation process was examined using a recently developed cell-free system in which dormant oxidase is activated by arachidonic acid in the presence of a soluble factor from the neutrophil (Curnutte, J. T. (1985) J. Clin. Invest. 75, 1740-1743). NADPH oxidase from unstimulated human neutrophils was detected only in the membrane fraction. The soluble activation factor was localized entirely to the cytosolic fraction and exhibited two peaks of activity when partially purified under nondenaturing conditions: a major peak with a molecular mass of approximately 250 kDa and a variable minor peak with a mass of approximately 40 kDa. Both forms activated NADPH oxidase in a similar manner and did not exhibit synergy when combined. The cytosolic factor is not protein kinase C (or another kinase) as both peaks of factor activity could be resolved from the protein kinase C peak and neither required calcium or ATP to activate the oxidase. Activation of NADPH oxidase did require the simultaneous presence of the membrane fraction, the cytosolic factor, arachidonic acid, and magnesium. Following activation, however, only the membrane fraction was then required for O2- production. Cytosolic factor levels were normal in five patients with either X-linked or autosomal recessive cytochrome b-negative chronic granulomatous disease. In contrast, the membrane fractions from each failed to generate O2-, indicating that the defects in these two genetic forms of chronic granulomatous disease reside either in the oxidase itself or in a membrane component required for activation.
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PMID:Activation of neutrophil NADPH oxidase in a cell-free system. Partial purification of components and characterization of the activation process. 357 Dec 24

Two proteins (Mr 46,000, pI 6.4 and 7.0), the phosphorylation of which was increased by any of the membrane-perturbing agents in parallel with activation of NADPH oxidase in intact guinea-pig polymorphonuclear leukocytes in our previous study (Okamura, N., Ohashi, S., Nagahisa, N. and Ishibashi, S. (1984) Arch. Biochem. Biophys. 228, 270-277), were also phosphorylated in a cell-free system prepared from the leukocytes. The in vitro phosphorylation of these two proteins was stimulated by the addition of phosphatidylserine in the presence of higher concentrations of Ca2+ (300-500 microM). The phosphorylation was further increased when protein kinase C partially purified from guinea-pig brain was added to the system. At a low concentration of Ca2+ (about 10 microM), stimulation of the phosphorylation was not attained by phosphatidylserine alone but required the addition of diacylglycerol or phorbol myristate acetate. On the other hand, the increase in the phosphorylation was inhibited by H-7, an inhibitor for protein kinase C. These results indicate that protein kinase C is involved in the phosphorylation of the two proteins, which may be related to the superoxide anion production stimulated by various membrane-perturbing agents.
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PMID:Involvement of protein kinase C in the phosphorylation of 46 kDa proteins which are phosphorylated in parallel with activation of NADPH oxidase in intact guinea-pig polymorphonuclear leukocytes. 375 25

A protein of 31.5 kDa belonging to the NADPH oxidase of neutrophils was phosphorylated following stimulation of the cells with phorbol myristate acetate. The same protein was phosphorylated in vitro in the presence of cytosol and of Ca2+ and phosphatidylserine. The phosphorylation in vitro of the 31.5 kDa protein was increased by phorbol myristate acetate and was inhibited by trifluoperazine. The data are compatible with an involvement of protein kinase C in the activation of NADPH oxidase.
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PMID:Protein kinase C phosphorylates a component of NADPH oxidase of neutrophils. 404 1

The paper deals with 1) the features of the respiratory burst (increase of the respiration with production of O2 metabolites, O2-, H2O2, OH) of the inflammatory cells; 2) the factors responsible for its activation; 3) the methods for its measurement; 4) the molecular events which take place at the level of the plasma membrane following the interaction between the stimuli and the cell surface (the Ca++ changes, the modification of membrane potential, the activation of phospholipid turnover) and the hypothesis of the activation of the protein kinase C; 5) the nature of the NADPH oxidase whose activation is responsible for the respiratory burst and the production of O2 metabolites; 6) the defensive, toxic, proinflammatory and modulatory effects due to the reactivity of the oxygen metabolites.
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PMID:Mechanism of production of toxic oxygen radicals by granulocytes and macrophages and their function in the inflammatory process. 405 21

We previously reported that phorbol 12-myristate 13-acetate (PMA)-induced superoxide (O2.-) generation of neutrophils was inhibited by hypericin, a photosensitizing pigment found in St. Johnswort (herb Hypericin triquetrifolium Turra), via a mechanism involving protein kinase C (PKC). To obtain further insights into the mechanism of inhibition, the effects of hypericin on stimulation-dependent O2.- generation and related enzymes of neutrophils were investigated. Hypericin inhibited O2.- generation of neutrophils induced by PKC-dependent and -independent stimuli in a light- and concentration-dependent manner. Oxygen was required for the light-dependent inhibition by hypericin. NADPH oxidase activity in a cell-free system and TNF-alpha-induced tyrosyl phosphorylation of neutrophil proteins were also inhibited by hypericin in a concentration- and light-dependent manner. However, tyrosine kinase of p60src, an enzyme not bound to a membrane, was not inhibited either in the light or in the dark. Oxygen uptake of neutrophils by photosensitization with hypericin resulted in the formation of singlet oxygen (1O2), O2.-, and hydroxyl radical (.OH) and enhanced lipid peroxidation. The formation of 1O2 was inhibited by azide, a quencher of 1O2, but not by desferrioxamine (DSF), a ferric ion chelator. By contrast, both generation of .OH and lipid peroxidation were inhibited by DSF but not by azide. Furthermore, PMA-induced O2.- generation inhibited by hypericin partially recovered in the presence of azide but not DSF. These results suggested that the light-dependent inhibition of O2.- generation by hypericin might be due to inhibition of tyrosine kinase, PKC, and NADPH oxidase via an oxygen-dependent mechanism, possibly through both Type I and II photosensitization mechanisms.
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PMID:Inhibition of neutrophil superoxide generation by hypericin, an antiretroviral agent. 748 96

We studied involvement of tyrosine-phosphorylated proteins in activation of NADPH oxidase in guinea pig neutrophils. Pervanadate, which is the oxidized form of orthovanadate, induced O2- production and protein tyrosine phosphorylation in neutrophils. O2- production induced by pervanadate was more sensitive to the tyrosine kinase-specific inhibitor, ST-638, as compared with the production induced by PMA. On the other hand, staurosporine more selectively inhibited PMA-induced O2- production than pervanadate-induced production. These results indicate that tyrosine kinase, not protein kinase C, is involved in pervanadate-induced O2- production. The tyrosine-phosphorylated proteins were detected in both the cytosol and membrane fractions prepared from pervanadate-induced neutrophils. In order to examine if tyrosine residues of some components of NADPH oxidase were directly phosphorylated, tyrosine-phosphorylated proteins were removed from solubilized membranes prepared from the pervanadate-stimulated neutrophils by immunoprecipitation with an anti-phosphotyrosine anti-body. NADPH oxidase activity in the solubilized membranes was not decreased by the treatment. These findings suggest that the components of NADPH oxidase are not tyrosine-phosphorylated by pervanadate treatment, that tyrosine phosphorylation may be involved in the signal transduction pathway of NADPH oxidase activation by pervanadate, and that this pathway is independent of the activation by protein kinase C.
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PMID:Respiratory burst and tyrosine phosphorylation by vanadate. 748 2

p47-phox is one of the cytosolic activation factors of NADPH oxidase in neutrophils and known to translocate to plasma membranes and function by protein kinase C-phosphorylation. In cytosol fraction, prepared from calyculin A-treated neutrophils, the activity of cytosolic factor to activate NADPH oxidase was more reduced than that from PMA-treated cells. But, p47-phox did not translocate to the membranes, even if p47-phox was hyperphosphorylated in the calyculin A-treated neutrophils. Such hyperphosphorylated p47-phox seemed to lose the activity to constitute NADPH oxidase complex.
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PMID:Hyperphosphorylated p47-phox lost the ability to activate NADPH oxidase in guinea pig neutrophils. 748 90

Phorbol ester (TPA) is generally considered to be a negative regulator of PtdIns-PLC activity. Here we show, for the first time, that the combination of TPA+ vanadate is a positive regulator (activator) of PtdIns-PLC in mouse elicited peritoneal macrophages. Vanadate or TPA on their own had no effect on PtdIns-PLC activity. In addition, TPA+ vanadate enhanced reactive oxygen species formation and protein tyrosine phosphorylation. PtdIns-PLC activation was suppressed by down regulation or inhibition of PKC, by inhibition of NADPH oxidase activity and scavenging of its product, and by inhibitors of protein tyrosine kinase activity. We conclude that PKC activation by TPA in the presence of vanadate activates the formation of reactive oxygen species, which are essential for the enhancement of protein tyrosine phosphorylation and eventually to PtdIns-PLC activation.
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PMID:Activation of macrophage PtdIns-PLC by phorbol ester and vanadate: involvement of reactive oxygen species and tyrosine phosphorylation. 751 Jan 6


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