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)

Protein kinase C (PKC) inhibitors, staurosporine or 1,5-isoquinolinesulfonyl)-2-methylpiperazine (H7), inhibited NADPH oxidase activity and phosphorylation of 47 kDa protein (p47) in PMA-stimulated neutrophils in a dose-dependent manner. These PKC inhibitors, at the same doses, did not affect oxidase activity and caused only partial inhibition of p47 phosphorylation in OZ-stimulated neutrophils. There was residual (20%) phosphorylated p47 in the membranes of OZ-stimulated cells in the presence of PKC inhibitors, at concentrations which caused total inhibition of oxidase activity and p47 phosphorylation in PMA-stimulated neutrophils. In the presence of ionomycin, which increased intracellular calcium ion concentrations, staurosporine was less effective in inhibiting both superoxide generation and p47 phosphorylation stimulated by PMA, similar to its effect in OZ-stimulated cells. The results indicate that some phosphorylation of p47 always accompanied oxidase activation induced by PMA or OZ, though the degree of phosphorylation of membrane-bound p47 does not directly correlate with rates of superoxide production.
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PMID:The requirement of p47 phosphorylation for activation of NADPH oxidase by opsonized zymosan in human neutrophils. 830 97

To further define the role played by protein kinase C (PKC) in the activation of the neutrophil NADPH oxidase, we have utilized a pseudosubstrate of PKC which was myristoylated at the N terminus. In electropermeabilized neutrophils, the myristoylated pseudosubstrate Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln (myr-psi PKC) inhibited PMA-induced protein phosphorylations and activation of the NADPH oxidase, induced either by PMA or by the receptor agonist formyl-methionyl-leucyl-phenylalanine. Both the pseudosubstrate lacking the N-terminal myristate (psi PKC) and a myristoylated control peptide (Phe-Ala-Glu-Asp-Gly-Ala-Leu-Glu-Gln, myr-CP) were without effect on these responses. The myristoylated pseudosubstrate was also tested in a cell-free system, in which NADPH oxidase activation can be achieved by addition of SDS and guanosine 5'-3-O-(thio)triphosphate in a staurosporine-insensitive manner. Myr-psi PKC, but not psi PKC or myr-CP, proved to be a potent inhibitor of NADPH oxidase activity in the cell-free system, indicating that the inhibition observed in permeabilized neutrophils may have been caused by an effect other than PKC inhibition. In the presence of myr-psi PKC, translocation in the cell-free system of the cytosolic oxidase components p47-phox and p67-phox to the plasma membrane was inhibited. From these results we conclude that myristoylation profoundly increases the ability of pseudosubstrates of PKC to inhibit not only PKC-mediated phosphorylations, but also NADPH oxidase activation. The latter effect, however, is most probably not related to PKC inhibition but may indicate a critical role of the membrane surface charge in the translocation of the cytosolic oxidase components p47-phox and p67-phox.
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PMID:Inhibition of neutrophil NADPH oxidase assembly by a myristoylated pseudosubstrate of protein kinase C. 836 Jan 54

The results presented in this paper demonstrate that the potentiation of phagocytosis of erythrocyte (E) IgG by TNF-alpha or PMA is not due to an oxygen-dependent mechanism. In fact, the potentiation of phagocytosis occurs normally in human neutrophils 1) when the respiratory burst is inhibited by diphenyleneiodonium, 2) in conditions where the reactive oxygen metabolites produced by the activation of NADPH oxidase, that accompanies the phagocytosis, were removed by catalase or superoxide dismutase, 3) of a patient lacking NADPH oxidase activity due to a genetic defect of p67-phox, 4) treated with staurosporine which allowed PMA to potentiate the ingestion of E-IgG at concentrations which inhibited the activation of the respiratory burst. Evidence is also presented that staurosporine not only did not inhibit, but amplified the potentiation of phagocytosis by PMA and TNF-alpha. This last finding suggests that the activation of protein kinase C plays a modulatory rather than a positive role in the mechanism of potentiation of phagocytosis.
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PMID:The potentiation by TNF-alpha and PMA of Fc receptor-mediated phagocytosis in neutrophils is independent of reactive oxygen metabolites produced by NADPH oxidase and of protein kinase C. 839 10

The effect of sulfite on the oxidative metabolism of human neutrophils was studied in vitro. Superoxide anion production of PMN was determined using superoxide dismutase-inhibitable lucigenin-dependent CL. The addition of sulfite in concentrations of 0.01 mM-1 mM results in an up to 6-fold increase in CL of nonstimulated neutrophils at 37 degrees C and pH 7. Neutrophils stimulated with zymosan or PMA have an additional 2-fold stimulation when sulfite is added. Higher sulfite concentrations (2 mM-10 mM) decrease the CL of both nonstimulated and stimulated cells. The activity of NADPH oxidase, responsible for O2.- production, is significantly increased in neutrophils incubated with 1 mM sulfite. Neutrophils from patients with chronic granulomatous disease, which are cytochrome b558 negative or have p47phox deficiency, exhibit no significant NADPH oxidase activity and show no increase in CL by sulfite. Inhibitors of protein kinase C, H7, and calphostin C, as well as inhibitors of Ca(2+)- and calmodulin-dependent processes, W7, and R 24 571, completely inhibited the increased CL of sulfite-treated neutrophils. These findings indicate that sulfite in low concentrations stimulates neutrophils to produce superoxide anions by activation of NADPH oxidase through a signal transduction pathway involving protein kinase C and Ca2+/calmodulin.
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PMID:Sulfite stimulates NADPH oxidase of human neutrophils to produce active oxygen radicals via protein kinase C and Ca2+/calmodulin pathways. 839 22

Infection is a frequent complication and the major cause of death among end-stage renal patients. Polymorphonuclear phagocytes (PMNL) are important in host defense mainly because of bacterial destruction by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-related free radical production following phagocytosis. In this study, hexose monophosphate pathway glycolytic activity, delivering energy to NADPH oxidase, is evaluated in vivo and in vitro, in healthy controls and in dialyzed renal failure patients. Our results show a marked parallel and correlated inhibition in the response to three stimuli for phagocytic activity (Staphylococcus aureus, formyl-methionine-leucine-phenylalanine, phorbol myristic acid) in predialysis samples. These data point to a main suppression of metabolic pathways, possibly beyond protein kinase C. This response is further suppressed at the 15th minute of cuprophane dialysis, for all stimuli studied (-40 to -94%; p < 0.001) except PMA. PMNL response remains intact during dialysis with non-complement-activating dialyzers. In vitro experiments confirm decreased PMNL glycolytic activity after the suspension of cuprophane fragments in normal whole blood. We conclude that polymorphonuclear cell energy delivery to NADPH oxidase is impaired in patients with end-stage renal failure. The impaired response against various stimuli is different in predialysis blood samples compared to samples collected during cuprophane dialysis, and may be related to two different conditions. These events probably contribute to the acquired immune suppression of uremia and the high incidence of infection among dialysis patients.
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PMID:Depressed phagocytosis in hemodialyzed patients: in vivo and in vitro mechanisms. 845 76

1. Neutrophil NADPH oxidase produces the superoxide anion (O2-) anion radical from oxygen. The thiol containing ACE inhibitor, captopril has been reported to inhibit isolated NADPH oxidase. The above effect of captopril, if present in intact cells, could contribute to the ability of this drug to alleviate neutrophil-mediated tissue damage. We have, therefore, investigated the effect of captopril on the oxidative activity of intact human isolated neutrophils. 2. The effects of captopril on neutrophil oxidative activity were compared with those of enalaprilat (a non-thiol ACE inhibitor) and N-mercaptopropionyl glycine (MPG) (a simple thiol). 3. The oxidative response of PMA-stimulated neutrophils measured by lucigenin chemiluminescence was not affected by any of these test agents. The thiol captopril and MPG (but not enalaprilat) caused an initial delay in luminol chemiluminescence production by PMA-stimulated neutrophils. 4. Captopril and MPG (but not enalaprilat) increased, rather than decreased oxygen uptake, when added to PMA-stimulated neutrophils. Thiol oxidation was determined to be, at least partly, responsible for the excess oxygen uptake observed. 5. NADPH oxidase activity in intact neutrophils was not affected by captopril, MPG or enalaprilat. The inhibition of NADPH oxidase activity is unlikely to contribute to the therapeutic effects of captopril and other thiols.
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PMID:Effect of captopril, enalaprilat and mercaptopropionyl glycine (MPG) on the oxidative activity of human isolated neutrophils. 852 65

Addition of GTPgammaS to saponin-permeabilised human neutrophils activated both the NADPH oxidase and phospholipase D (PLD). This PLD activation was hardly affected by staurosporine or Ro31-8220 (at concentrations which inhibited PMA stimulated PLD activity), indicating that it was largely independent of protein kinase C (PKC). This GTPgammaS stimulated PLD activity was enhanced by 1 mM ATP, but this ATP-enhanced activity was blocked by inhibitors of PKC. Addition of GTPgammaS resulted in very low levels of phosphorylation on tyrosine residues, but higher levels of phosphorylation on serine/threonine residues. Addition of pervanadate hydroperoxides stimulated phosphorylation on tyrosine residues and activated PLD which was blocked by addition of inhibitors of tyrosine kinases. Thus, GTPgammaS can stimulate PKC-dependent and -independent pathways of PLD activation. Whilst phosphorylation on tyrosine residues can result in activation of PLD, this is regulated independently of activation via G-proteins.
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PMID:GTPgammaS-stimulated phospholipase D activation in human neutrophils occurs by protein kinase C-dependent and -independent pathways but not tyrosine kinases. 860 92

Protein kinases are stimulated during the microbicidal responses of neutrophils. In particular, the activation of protein kinase C causes the phosphorylation of p47-phox, one of the cytosolic components of NADPH oxidase. Phosphorylated p47-phox was accumulated not only by PMA treatment, but also by calyculin A treatment. However, p47-phox phosphorylated by calyculin A treatment lost its ability to activate NADPH oxidase. Several protein kinases were activated by calyculin A treatment. Furthermore the phosphorylation sites of p47-phox by calyculin A treatment were different from those by PMA treatment. These results indicated that calyculin A-activated kinases phosphorylated p47-phox at the site different from that phosphorylate by protein kinase C, resulting in suppression of NADPH oxidase activation.
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PMID:Involvement of several protein kinases in the phosphorylation of p47-phox. 860 62

In response to formyl-Met-Leu-Phe (fMLP), human neutrophils (PMN) generate superoxide anion (O2-) by the enzyme complex NADPH oxidase. The modulation of phosphoinositide (PPI) turnover and the activation of phospholipases C (PLC) and D (PLD) have been shown to be early steps in the oxidative response of fMLP-stimulated PMN. Although the physiological nonapeptide bradykinin (BK) is involved in inflammation, its participation in PMN activation has not been properly studied. In this work, activation of signal transduction pathways that mediate the oxidative response, and the modulation of the NADPH oxidase activity by BK, are analyzed. A direct comparison between the signal transduction pathway induced by BK and fMLP is also made. BK was not able to elicit O2- production by PMN. Nevertheless, several signal transduction pathways associated with PMN activation were triggered by BK. The nonapeptide induced the phosphorylation of prelabeled membrane PPI. This phenomenon was imitated by PMA and inhibited by H7 and staurosporine, thus suggesting the participation of protein kinase c (PKC). A loss of labeled [32P]PPI was triggered by fMLP. The fact that both PMA and fMLP stimulated O2- production but modulated PPI turnover in different ways, indicates that PPI labeling does not correlate with the oxidative response. Because PKC activation seemed to be a prerequisite for BK-induced modulation of PPI turnover, PLC activation could act as an intermediate step in this mechanism. Our results show that BK activated a PIP2-PLC measured as the release of [3H]IP3. On the contrary, a PC-PLD was highly stimulated by fMLP but not by BK. The fact that BK induced PLC activity but neither that of PLD nor NADPH oxidase, whereas fMLP triggered the activation of both phospholipases and evoked the PMN respiratory burst, suggests that diacylglycerol (DAG) from PIP2 as well as PA or PA-derived DAG, synergize to trigger the PMN oxidative response. Finally, BK inhibited O2- production by fMLP-activated PMN in a time-dependent manner. Since BK did not induce NO production by PMN, the inhibitory effect on the oxidative function was not due to ONOO- formation. These data show that BK plays an important role in inflammation by modulating the PMN function.
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PMID:Bradykinin stimulates phosphoinositide turnover and phospholipase C but not phospholipase D and NADPH oxidase in human neutrophils. 861 9

Src homology 3 (SH3) domains mediate specific protein-protein interactions crucial for signal transduction and protein subcellular localization. Upon phagocyte stimulation, two SH3 domain-containing cytosolic components of the NADPH oxidase, p47phox and p67phox, are recruited to the membrane where they interact with flavocytochrome b558 to form an activated microbicidal oxidase. Deletion analysis of p47phox and p67phox in transfected K562 cells demonstrated multiple SH3-mediated interactions between p47phox and the transmembrane flavocytochrome b558 and also between the cytosolic components themselves. The core region of p47phox (residues 151-284), spanning both SH3 domains, was required for flavocytochrome-dependent translocation and oxidase activity in whole cells. Furthermore, translocation of p67phox occurred through interactions of its N-terminal domain (residues 1-246) with p47phox SH3 domains. Both of these interactions were promoted by PMA activation of cells and were influenced by the presence of other domains in both cytosolic factors. Deletion analysis also revealed a third SH3 domain-mediated interaction involving the C-termini of both cytosolic factors, which also promoted p67phox membrane translocation. These data provide evidence for a central role for p47phox in regulation of oxidase assembly through several SH3 domain interactions.
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PMID:Multiple SH3 domain interactions regulate NADPH oxidase assembly in whole cells. 863 53


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