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)

A cDNA expression library from pig blood neutrophils was immunoscreened with a rabbit antiserum raised against a 32 kDa neutrophil membrane phosphoprotein. Previous work indicated this protein as a component of the superoxide-forming NADPH oxidase enzyme complex (1,2). Only one cDNA clone (B+) was highly positive. The B+ clone contained a 1109 bp insert, with an open reading frame encoding for 284 amino acids. The deduced B+ amino acid sequence contained a 72 amino acid domain with proline and glutamine repeats and two domains extremely enriched with serine residues. The isolated cDNA hybridizes with a 3.1 kb mRNA expressed in pig and human leukocytes.
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PMID:Isolation and characterization of a cDNA clone for a novel serine-rich neutrophil protein. 169 79

The control of potentially periodontopathic microorganisms by host neutrophils is crucial to periodontal health. Neutrophils may use oxidative or nonoxidative mechanisms and either kill bacteria, influence bacterial growth, or modify bacterial colonization in the periodontium. Delivery of antimicrobial substances by neutrophils involves respiratory burst activity, phagocytosis, secretion, or cytolysis/apoptosis. Neutrophils contain a number of antimicrobial components including calprotectin complex, lysozyme, defensins, cofactor-binding proteins, neutral serine proteases, bactericidal/permeability increasing protein, myeloperoxidase, and a NADPH oxidase system. Many of these components are multifunctional and exhibit several mechanisms of antimicrobial activity. When comparisons are made among periodontal bacteria, differences in sensitivity to different components are observed. A hypothesis of specific defense is presented: That specific periodontal diseases can result from the failure of specific aspects of the host immune system (the neutrophil, in particular) in its interaction with specific periodontal pathogens. Failure may be due to phenotypic variation (pleomorphism) within the host or bacterial evasive strategies.
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PMID:The neutrophil: mechanisms of controlling periodontal bacteria. 176 39

The superoxide (O2-)-forming NADPH oxidase of resting macrophages can be activated in a cell-free system by certain anionic amphiphiles, such as sodium dodecyl sulfate (SDS). O2- production requires the cooperation of membrane-associated and cytosolic components. The membrane component can be solubilized by octyl glucoside yielding a highly active oxidase preparation. High performance gel filtration of the solubilized oxidase on Superose 12 in the presence of 40 mM octyl glucoside leads to the total loss of enzymatic activity. This can be restored in previously inactive eluate fractions by "reconstitution" with N-ethylmaleimide or heat (60 degrees C)-inactivated total solubilized membrane. Oxidase activity, that becomes evident upon reconstitution, is eluted from Superose 12 with molecules in the Mr range of 300,000-71,000. The material with reconstitutive capacity is completely dissociated from the oxidase, eluting with molecules in the Mr range of 71,000-11,000. The Superose 12 elution profile of the material responsible for reconstitution coincides with that of membrane-derived phospholipid. Also, the reconstitutive capacity of total solubilized membrane and that of the Mr 71,000-11,000 region of the Superose eluate are recovered in a chloroform extract prepared by the method of Bligh and Dyer. It is concluded that loss of oxidase activity by gel filtration at a high octyl glucoside concentration is the consequence of delipidation. NADPH oxidase activity, revealed by reconstitution of Superose 12 fractions with exogenous phospholipid, correlates closely with the elution profile of cytochrome b559. Reconstitution of activity of delipidated oxidase can also be achieved with natural non-macrophage phospholipids and with synthetic phospholipids. Reconstitution of NADPH oxidase activity by lipids is governed by the following rules: (a) phospholipids are effective; lysophospholipids and neutral lipids are not; (b) phospholipids with polar heads represented by choline, ethanolamine, and serine, as well as cardiolipin, are effective; phosphatidylinositol is much less active; (c) phospholipids with unsaturated fatty acid residues are capable of reconstitution while saturated acyl residues do not confer activity; this specificity appears not to be related to the transition temperature of the phospholipids.
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PMID:Activation of the superoxide forming NADPH oxidase in a cell-free system by sodium dodecyl sulfate. Absolute lipid dependence of the solubilized enzyme. 254 2

Superoxide anion production by polymorphonuclear leukocytes stimulated with phorbol 12-myristate 13-acetate is known to be inhibited by a number of inhibitors and substrates of serine proteases, in particular by tosylphenylalanylchloromethane (TosPheCH2Cl) and to a lesser extent by tosyllysylchloromethane (TosLysCH2Cl). We have reinvestigated the characteristics of this inhibition, in view of the fact that other serine protease inhibitors with similar specificities, phenylmethanesulfonyl fluoride and leupeptin, were without effect. We found that the inhibition of phorbol-ester-induced superoxide production after cell preincubation with the chloromethanes followed saturation kinetics, with Kinact and kinact values of 100 microM and 31 min-1 for TosPheCH2Cl and 2 mM and 18 min-1 for TosLysCh2Cl. We also showed that the two compounds, which can inhibit protein kinase C in vitro, inhibited neither its activity in vivo, nor its translocation induced by phorbol myristate acetate. Furthermore the intracellular non-protein sulfhydryl group content was not affected by the treatment with the chloromethanes. Finally, addition of the inhibitors to stimulated cells also led to a time-dependent, concentration-dependent inhibition of superoxide production. Altogether, our results suggest that the chloromethane target is neither a protease nor protein kinase C and is not involved in NADPH oxidase activation, but rather in maintenance of its activity. The possible identity of this protein is discussed.
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PMID:Inhibition of NADPH oxidase by aminoacyl chloromethane protease inhibitors in phorbol-ester-stimulated human neutrophils: a reinvestigation. Are proteases really involved in the activation process? 254 67

Daphnoretin, a dicoumarin isolated from Wikstroemia indica C.A. Mey. (Thymelaceae), induced superoxide anion (O2-) formation in rat neutrophils in a concentration-dependent manner. Addition of staurosporine reduced daphnoretin-induced respiratory burst. Removal of extracellular free Ca2+ by EGTA did not affect the respiratory burst of neutrophils in response to daphnoretin. Prior exposure of neutrophils to phorbol 12-myristate 13-acetate (PMA) or daphnoretin reduced the O2- formation caused by a subsequent challenge with PMA and daphnoretin, but potentiated the response caused by a subsequent addition of formyl-Met-Leu-Phe (fMLP). Like PMA, daphnoretin did not increase the [Ca2+]i during cell activation. In neutrophil suspension, daphnoretin increased the membrane associated protein kinase C activity. In the presence of Ca2+ and phosphatidyl-serine, daphnoretin also activated protein kinase C isolated from cytosolic fraction of resting neutrophils. Staurosporine inhibited the direct activation of protein kinase C caused by daphnoretin as well as by PMA. Daphnoretin reduced the [3H]Phorbol-12,13-dibutyrate ([3H]PDB) binding to the neutrophil cytosolic protein kinase C in a concentration-dependent manner with an IC50 value of 1.77 +/- 0.37 microM. These results indicate that daphnoretin, like PMA, may direct activation of protein kinase C which in turn activated NADPH oxidase and elicited respiratory burst.
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PMID:Daphnoretin-induced respiratory burst in rat neutrophils is, probably, mainly through protein kinase C activation. 777 78

Endotoxemia, in man, has been associated with an autooxidative reduction in the bioavailability of polymorphonuclear leukocyte receptors. The location and mechanisms of this phenomena have remained unclear; we investigated the effects of lipopolysaccharide (LPS) on intracellular Fc gamma receptor expression. Polymorphonuclear leukocytes (PMN) were incubated with LPS (10 ng/ml), permeabilized with saponin, followed by measurement of CD64, CD32w, and CD16 (Fc gamma RI, II, III) using 125I-monoclonal antibodies directed against these receptors. Exposure of permeabilized PMN to LPS significantly reduced intracellular Fc gamma receptor expression. PMN isolated from patients with chronic granulomatous disease or myeloperoxidase-specific deficiency did not exhibit this effect. Furthermore, specific inhibitors of components of the PMN oxidative burst (NaN3, 10 mM; L-alanine 30 mM) prevented the LPS-induced oxidative reduction in receptor expression. NADPH oxidase inhibition with diphenyleneiodonium also blocked the effect of LPS on intracellular Fc gamma receptor expression. The effects of LPS on intracellular PMN Fc gamma receptors were reproduced with monophosphoryl lipid A but required a 10 times greater concentration than LPS. Preadherence of PMN on fibronectin or arginine-glycine-aspartate-serine (RGDS), but not laminin, prevented the LPS-induced reduction in oxidative receptor expression. The effects of fibronectin/RGDS were blocked by actinomycin D and cycloheximide. Cross-linkage of intracellular Fc gamma receptors prior to exposure to LPS also prevented the LPS-induced oxidative reduction in receptor expression. These results demonstrate that an important pathophysiologic property of LPS is to induce an intracellular oxidative-derived reduction in Fc gamma receptor expression and that the biologically relevant proteins fibronectin and RGDS ameliorate this effect.
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PMID:Regulation of intracellular polymorphonuclear leukocyte Fc receptors by lipopolysaccharide. 806 31

Production of reactive oxygen metabolites by the NADPH oxidase is an essential mechanism underlying the microbicidal role of phagocytes. Receptor-mediated activation of the oxidase was originally thought to be mediated by calcium and/or by protein kinase C (PKC). However, recent evidence suggests that additional signalling pathways exist. In this article the possible role of tyrosine phosphorylation is discussed. In addition, results obtained using an in vitro kinase renaturation assay are described. The latter assay revealed the existence of at least four serine/threonine kinases that are activated in cells stimulated with chemoattractants. One of these, of molecular weight 41,000 was identified as a member of the ERK or MAP-kinase family. The existence of multiple, possibly redundant or synergistic signaling pathways is considered.
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PMID:Involvement of multiple kinases in neutrophil activation. 831 67

The non-12-O-tetadecanoylphorbol-13-acetate (TPA)-type tumor promoters, okadaic acid (OA) and calyculin-A (CAL-A), which neither interact with the phorbol ester receptor nor directly activate protein kinase C, mimic the stimulatory effects of and thapsigargin on hydroperoxide (HPx) production in mouse epidermis in vivo. The time course and dose dependency for the stimulation of HPx production by O and TPA are similar. HPx production is maximally stimulated 16 h after two applications of 2 nmol of OA at a 48-h interval. However CAL-A is a stimulator of HPx production about 4 times more potent than OA or TPA. Combinations of TPA and OA or CAL-A have subadditive effects on HPx production. The discrepancies between the abilities of various serine/threonine protein phosphatase (PP) inhibitors to stimulate HPx production suggest that PP inhibition alone is not sufficient for this response. Cycloheximide, Ca2+ antagonists, oxypurinol, diphenyliodonium, nordihydroguaiaretic acid, bromophenacyl bromide, antiinflammatory agents, and antihistamines block or decrease OA-stimulated HPx production. Although most of these inhibitors may have more than one action, their effects suggest that protein synthesis, Ca2+, xanthine oxidase and NADPH oxidase activities, the lipoxygenase pathway of arachidonic acid metabolism, and vascular permeability may be involved in the inflammatory and HPx responses that occur after tumor promoter treatment. The increased HPx-producing activity of the epidermis, therefore, may be a common event resulting from the inflammatory and tumor-promoting actions of diverse TPA- and non-TPA-type agents.
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PMID:Ability of okadaic acid and other protein phosphatase inhibitors to mimic the stimulatory effects of 12-O-tetradecanoylphorbol-13-acetate on hydroperoxide production in mouse epidermis in vivo. 855 15

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

We examined the effects of okadaic acid, a protein phosphatase 1 and 2A inhibitor, on superoxide generation in human neutrophils. Superoxide generation induced by fMLP was inhibited by low-dose okadaic acid (10-100 nM), but it had no effect on superoxide synthesis by PMA, and the fMLP-induced rise of the intracellular Ca2+ concentration was not affected by low-dose okadaic acid. These findings suggested that the inhibitory mechanism of okadaic acid might involve PKC-independent and Ca(2+)-independent pathways in fMLP induced NADPH oxidase activation. Both fMLP-stimulated phosphorylation of serine residues in p47phox and its translocation to the plasma membrane were suppressed by low-dose okadaic acid. On the other hand, PMA-induced phosphorylation and translocation of p47phox were not affected by such a low dose of okadaic acid. These findings suggested that fMLP induced phosphorylation of serine residues in p47phox was regulated by protein phosphatase 2A, and its phosphorylation was necessary for translocation and superoxide generation in fMLP-activated human neutrophils.
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PMID:Involvement of protein phosphatase 2A in PKC-independent pathway of neutrophil superoxide generation by fMLP. 865 38


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