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)

This article gives a synopsis of the inflammatory reactions as well as its mediators under special consideration of the efferent part of the reaction. There is no doubt that histamine, complement, and the kinin system play an essential role; arachidonic acid (eicosatetraenic acid) and its metabolites, however, have gained comparable significance: prostaglandines, prostacyclines, and thromboxanes as metabolites of the cyclo-oxygenase, the leucotrienes SRS-A (slow reacting substances of anaphylaxis) and ECF (eosinophilic chemotactic factor) mediated via lipoxygenase. Moreover, oxygen and its metabolites hydrogen peroxide (H2O2), peroxide radicals (O-2), and hydroxyl radicals (.OH) as well as activated oxygen (singulett oxygen (1O2) play an important part with all aerobic living organisms. Inborn enzyme deficiency of the oxygen metabolism such as NADPH oxidase or cytochrome b-245 deficiency lead to chronic septic granulomatosis. The disease is characterized by reduced resistence against infections, decreased phagocytosis, insufficient killing of bacteria by leucocytes, and diminished oxygen burst. Thus the underlying enzyme deficiency leads to reduced formation of peroxide radicals frequently causing infections with septic complications. On the other hand, increased formation or reduced degradation of peroxide radicals may result in pathological reactions like chromosomal alterations, lipidperoxidation or oxidation of sulph-hydryl groups. The fact that increased peroxide radical formation may cause inflammation or chromosomal aberration is of importance with regard to the pathogenesis of several chronic inflammatory diseases of unknown etiology, such as systemic scleroderma or lupus erythematodes. The enzyme superoxide dismutase (SOD) converts peroxide radicals (O-2) into hydrogen peroxide (H2O2) which can be inactivated by catalase or peroxidase. Consequently, treatment with SOD may have an effective influence on chronic inflammatory dermatoses of unknown pathogenesis.
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PMID:[Biochemical aspects of the inflammatory reaction - with special reference to oxygen]. 666 95

Human neutrophils were fractionated by nitrogen cavitation and Percoll density centrifugation, and the subcellular localization of FAD-flavoprotein, b-cytochrome, NADH-cytochrome b5 reductase, and NADPH-dependent cytochrome c reductase were determined in normal cells, cells from two patients with chronic granulomatous disease (CGD), and normal cells that had been stimulated with phorbol myristate acetate. In normal cells, a FAD-flavoprotein is found in a 1:2 molar ratio, with cytochrome b in the fractions containing the specific granules. Triton X-114 phase distribution indicates that the b-cytochrome but not the b-cytochrome-associated flavoprotein is an integral membrane protein. 80% of this flavoprotein, as well as all the b-cytochrome, was absent in these fractions from 2 CGD patients, although these patients had normal quantities of FAD in the fractions containing plasma membranes and cytosol. During stimulation the b-cytochrome-associated flavoprotein of the granules translocates with the b-cytochrome to the plasma membrane where NADPH oxidase is localized. Definition of the role of these NADPH oxidase constituents may provide a molecular description of the normal neutrophil respiratory burst and the molecular defect(s) in CGD.
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PMID:Subcellular localization of the human neutrophil NADPH oxidase. b-Cytochrome and associated flavoprotein. 670 48

NADPH-dependent O2- forming activity was extracted with deoxycholate from subcellular particles of guinea-pig neutrophils following stimulation with phorbol myristate acetate. The solubilized enzyme was purified by chromatography on Ultrogel AcA22, by isopycnic glycerol density gradient centrifugation and by treatment with 0.4 M NaCl. This procedure yielded a high-molecular-weight complex containing phospholipids, cytochrome b-245 and NADPH oxidase activity. Cytochrome b was found to be purified to the same extent as NADPH oxidase activity. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the various purification fractions showed a progressive enrichment of a band whose molecular weight is 3.2 X 10(4). The enrichment of this protein band paralleled those of NADPH oxidase activity and of cytochrome b, indicating that it is a component of the oxidase system. The possibility that this band corresponds to either cytochrome b or a flavoprotein/cytochrome b complex is considered.
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PMID:Isolation from neutrophil membranes of a complex containing active NADPH oxidase and cytochrome b-245. 674 61

NADPH oxidase from stimulated guinea pig granulocytes was extracted with deoxycholate. The solubilized enzyme was stable in 20% glycerol. Solubilized enzyme was free of myeloperoxidase activity. The properties of the deoxycholate solubilized enzyme indicated that it is a high molecular weight complex with a flavoprotein, calmodulin and cytochrome b possibly forming part of the complex. Maximum activity was between pH 7.0 and 7.5. The Km value was 15.8 microM for NADPH and 434 microM for NADH indicating that NADPH is the preferential substrate.
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PMID:The NADPH oxidase of guinea pig polymorphonuclear leucocytes. Properties of the deoxycholate extracted enzyme. 686 30

NADPH-dependent O2- -generating activity was extracted and partially purified from guinea pig polymorphonuclear leukocytes. The most active preparation generated 202.8 nmol O2- min/min per mg protein. This activity was 30-fold higher than that of extracts from resting cells, indicating that the activated state of the oxidase was retained after solubilization. The solubilization and purification of the enzyme activity were followed by a parallel solubilization and purification of cytochrome b. Spectroscopic studies showed that solubilized cytochrome b has an Em of -245 mV and binds CO to about 30%. Cytochrome b was reduced by NADPH in anaerobiosis at a low rate and was rapidly reoxidized by air. A correlation was found between the inhibition of O2- formation caused by the SH reagent p-chloromercuribenzoate and the alterations induced by this compound on the Em of cytochrome b. These observations strongly support the participation of cytochrome b in the catalytic activity of the solubilized NADPH oxidase. The enzyme preparations contained FAD, which was found to be associated both with NADPH oxidase and with diaphorase activities. The fraction with the highest O2- forming activity contained FAD and cytochrome b in a ratio of about 0.5:1. The participation of FAD in the electron transport from NADPH to O2 is supported also by the inhibitory effect exerted by quinacrine on O2- formation.
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PMID:The cytochrome b and flavin content and properties of the O2- -forming NADPH oxidase solubilized from activated neutrophils. 687 Dec 31

Phagocytic cells can kill microorganisms by synthesizing superoxide. Activation of the NADPH oxidase that generates superoxide is accompanied by a large intracellular burst of metabolic acid production. Despite the excess acid generation, cytosolic pH (pHi) remains near neutrality due to the concomitant stimulation of several homeostatic H+ extrusion mechanisms including a recently described H(+)-conductive pathway. Activation of the conductance by phorbol esters is defective in neutrophils of chronic granulomatous disease (CGD) patients lacking the transmembrane cytochrome b subunits of the NADPH oxidase. This finding suggests that the oxidase itself undertakes H+ translocation or that, alternatively, assembly of the oxidase is required to activate a separate H+ conducting entity. To distinguish between these possibilities, the presence of the conductive pathway was assessed in unstimulated normal and CGD cells by manipulating pHi and the transmembrane potential. Using fluorimetric determinations of pHi, a conductive, Zn(2+)-sensitive alkalinization was observed in neutrophils from both normal and cytochrome b-deficient CGD donors. The electrophysiological properties of the conductance were defined in purified blood monocytes using the whole cell configuration of the patch clamp. Depolarizing pulses induced slowly activating outward currents in cells from both normal and cytochrome b-deficient individuals. The elicited currents were potentiated by cytosolic acidification and did not inactivate within the times tested. As in control leukocytes, the reversal potential of tail currents in the CGD cells closely approximated the H+ equilibrium potential and was unaffected by substitution of the major ionic components of the external bathing medium. At all voltages tested, the magnitude of the evoked currents was comparable in normal and CGD cells. The results indicate that, like macrophages and granulocytes, human monocytes display a voltage-gated highly H(+)-selective conductance. More importantly, our findings imply that the conductive pathway is present in cells devoid of cytochrome b. Therefore, the defective activation of the conductive pathway by protein kinase C agonists in CGD cells is not due to the physical absence of the transporter. Instead we propose that the oxidase functions in a regulatory capacity, facilitating the opening of a distinct H+ conductance during cellular stimulation.
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PMID:Assessment of the contribution of the cytochrome b moiety of the NADPH oxidase to the transmembrane H+ conductance of leukocytes. 752 51

Recent studies have shown that the NADPH oxidase participates in the generation of superoxide anion in non-phagocytic cells. Here we report the isolation and nucleotide sequence of a cDNA for the cytochrome b-558 alpha-subunit of the NADPH oxidase in rat vascular smooth muscle cells (VSMCs). The coding region of the cDNA was 93% homologous to mouse and 81% to human in nucleotide sequence and 96% homologous to mouse and 89% to human in the deduced amino acid sequence. Our results provide a tool with which to explore the mechanism of superoxide anion generation in rat VSMCs and other non-phagocytic cells.
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PMID:Cytochrome b-558 alpha-subunit cloning and expression in rat aortic smooth muscle cells. 757 11

Cytosolic components of the phagocyte NADPH oxidase (p47phox, p67phox, and Rac2) translocate to the plasma membrane on cell activation where they interact with a membrane-bound cytochrome b to generate superoxide anion. Phosphorylation reactions are known to be important for activity of NADPH oxidase. Translocation of Rac2, p47phox, and p67phox were all enhanced in formyl-Met-Leu-Phe-stimulated neutrophils treated with 50 nM of the protein phosphatase 1/2A inhibitor calyculin A. Rac translocation was blocked by the tyrosine kinase inhibitors genistein (50 microM) and herbimycin (17 microM), whereas movement of p47phox and p67phox were not inhibited. Cell-free analysis of Rac translocation also demonstrated that translocation of p47phox and p67phox were not linked to the movement or availability of Rac2. Thus, Rac2 does not appear to regulate NADPH oxidase by controlling movements of the cytosolic components to the membrane-associated enzyme but may exert its effect at the level of the assembled complex. Tyrosine kinase activity is required for translocation of Rac in the chemoattractant-stimulated human neutrophil.
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PMID:Dissociation of Rac translocation from p47phox/p67phox movements in human neutrophils by tyrosine kinase inhibitors. 761 2

We have demonstrated that human fibroblasts can release O2-. radicals by an NADPH oxidase system that appears to be functionally similar to the phagocytic system. Further analysis of these systems, however, with respect to the low-potential b-type cytochromes involved suggests that these two O2-.-generating systems are not structurally identical. Immunoblot analysis of fibroblast membranes with six different antibodies directed against both subunits of human neutrophil cytochrome b-558 indicated that the b-type cytochrome molecules involved in these systems were not identical. None of these anti-(neutrophil cytochrome b) antibodies recognized a similar cytochrome in fibroblast membranes, suggesting that the two cytochrome species are immunologically distinct. In addition, fibroblasts obtained from a patient suffering from X-linked chronic granulomatous disease (CGD) had a normal cytochrome b-558 content compared with control fibroblast membranes, whereas the cytochrome b-558 concentration in polymorphonuclear leucocytes (PMNs) from this patient was decreased to 10% of that found in PMNs from healthy controls. Likewise, the stimulated O2-. release in PMNs from this patient was less than 10% of that in control PMNs, whereas the fibroblasts showed stimulated O2-.-release rates that were indistinguishable from those of fibroblasts obtained from healthy persons. Since the genetic mutation responsible for this type of CGD results in the absence of cytochrome b-558 in PMNs, fibroblasts should be affected in the same way if both cytochrome species were identical. These results suggest therefore that the low-potential b-type cytochromes in PMNs and fibroblasts are structurally and genetically distinct.
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PMID:The cytochrome b-558 molecules involved in the fibroblast and polymorphonuclear leucocyte superoxide-generating NADPH oxidase systems are structurally and genetically distinct. 767 34

Previous work has shown that human mesangial cells (HMC) are capable of low rates of generation of reactive oxygen species for considerable periods of time. In this communication, the presence of components of an NADPH oxidase-like system, more commonly associated with phagocytic leukocytes, is shown. The ability of HMC to generate low levels of superoxide may have important implications in cellular signaling in general and may contribute to glomerular injury. Spectroscopic analysis of HMC membranes revealed a low-potential cytochrome b component, redox midpoint potential centered around -250 mV, which is present at 60 pmol/mg of membrane protein. Immunodetection studies suggested the presence of the p22phox, p47phox, and p67phox components of the NADPH oxidase, whereas the gp91phox was not detected. Further studies with oligonucleotide polymerase chain reaction primers showed that, in HMC the mRNA expression of the p67phox and p47phox was absent from growth-arrested cells but was present in HMC treated with interleukin-1 beta (1,000 pg/mL), whereas gp91phox could not be detected. Only mRNA corresponding to p22phox was present in growth-arrested cells; p47phox mRNA was induced by 2-h treatment with interleukin-1 beta but declined after 6-h treatment. These data illustrate for the first time that HMC are capable of expressing mRNA for several NADPH oxidase components. The apparent absence, or variation, of the gp91phox indicates the likelihood of an NADPH oxidase isoenzyme.
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PMID:The expression of NADPH oxidase components in human glomerular mesangial cells: detection of protein and mRNA for p47phox, p67phox, and p22phox. 770 87


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