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)

The superoxide-producing phagocyte NADPH oxidase consists of a membrane-bound flavocytochrome b(558), the cytosol factors p47(phox), p67(phox), p40(phox), and the small GTPase Rac2, which translocate to the membrane to assemble the active complex following neutrophil activation. Interleukin-8 (IL-8) does not activate NADPH oxidase, but potentiates the oxidative burst induced by stimuli such as formyl-methionyl-leucyl-phenylalanine (fMLP) via a priming mechanism. The effect of IL-8 on the components of NADPH oxidase during the priming process has never been investigated in human neutrophils. Here we showed that within 3 min, IL-8 treatment enhanced the Btk- and ERK1/2-dependent phosphorylation of p47(phox), as well as the recruitment of flavocytochrome b(558), p47(phox), and Rac2 into cholesterol-enriched detergent-resistant microdomains (or lipid rafts). Conversely, IL-8 treatment lasting 15 min failed to recruit flavocytochrome b(558), p47(phox), or Rac2, but did enhance the Btk- and p38 MAPK-dependent phosphorylation and the translocation of p67(phox) into detergent-resistant microdomains. Moreover, methyl-beta-cyclodextrin, which disrupts lipid rafts, inhibited IL-8-induced priming in response to fMLP. Our findings indicate that IL-8-induced priming of the oxidative burst in response to fMLP involves a sequential assembly of the NADPH oxidase components in the lipid rafts of neutrophils.
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PMID:Interleukin-8-induced priming of neutrophil oxidative burst requires sequential recruitment of NADPH oxidase components into lipid rafts. 1611 78

Reactive oxygen species (ROS) are conventionally regarded as inevitable deleterious by-products in aerobic metabolism with a few exceptions such as their significant role in host defense. The phagocyte NADPH oxidase, dormant in resting cells, becomes activated during phagocytosis to deliberately produce superoxide, a precursor of other microbicidal ROS, thereby playing a crucial role in killing pathogens. The catalytic center of this oxidase is the membrane-integrated protein gp91(phox), tightly complexed with p22(phox), and its activation requires the association with p47(phox), p67(phox), and the small GTPase Rac, which normally reside in the cytoplasm. Since recent discovery of non-phagocytic gp91(phox)-related enzymes of the NAD(P)H oxidase (Nox) family--seven homologues identified in humans--deliberate ROS production has been increasingly recognized as important components of various cellular events. Here, we describe a current view on the molecular composition and post-translational regulation of Nox-family oxidases in animals.
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PMID:Molecular composition and regulation of the Nox family NAD(P)H oxidases. 1615 95

Oxidized LDL (OxLDL) is a proatherogenic lipoprotein, accumulating in the vascular wall and contributing to the pathogenesis of vascular dysfunction early in the development of atherosclerosis. Enhanced serum levels of OxLDL, as well as antibodies against its epitopes, are predictive for endothelial dysfunction and coronary heart disease. While enhanced oxidative stress is one factor triggering formation of OxLDL, OxLDL itself has been identified as a potent stimulus for vascular oxygen radical formation, causing a vicious circle. OxLDL-induced O(2)(-) formation, largely through activation of NADPH oxidase, but also through uncoupling of endothelial NO-synthase and through direct O(2)(-) release, leads to endothelial dysfunction. Furthermore, OxLDL-induced O(2)(-) formation has a strong impact on tissue remodeling, resulting in either cell growth - proliferation or hyperplasia - or apoptotic cell death. The effect of OxLDL on cell cycle regulation is mediated by activation of the small GTPase RhoA and consequent regulation of p27(KIP1), a key enzyme of the cell cycle. In addition, OxLDL-induced activation of RhoA sensitizes the contractile apparatus of the vessel wall, enhancing the contractile tonus and favoring vasospasm. Thus, through a variety of mechanisms, OxLDL importantly contributes to vascular dysfunction and remodeling.
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PMID:Impact of oxidized low density lipoprotein on vascular cells. 1628 60

The membrane-integrated protein gp91phox functions as the catalytic center of the superoxide-producing phagocyte NADPH oxidase. Recent studies have identified homologs of gp91phox in nonphagocytic cells, which constitute the NADPH oxidase (Nox) family. Activation of the Nox oxidases leads to production of reactive oxygen species (ROS), thereby participating in a variety of biological events, such as host defense, hormone biosynthesis, and signal transduction. The activity of the Nox enzymes is regulated by various proteins, including the small GTPase Rac; regulatory mechanisms differ dependent on the type of the Nox proteins. For example, an oxidase activator (p47phox or Noxo1) and an oxidase activator (p67phox or Noxa1) are absolutely required for superoxide production by gp91phox and Nox1, but not by Nox3. Rac, albeit probably dispensable to the Nox3 activity, plays an essential role in activation of gp91phox. Thus, functional reconstitution of Nox systems is crucial for the study of Nox regulation. Here we describe a basic method for the reconstitution of Nox systems by expression of oxidase proteins in transfectable cells.
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PMID:Regulation of superoxide-producing NADPH oxidases in nonphagocytic cells. 1647 78

Microglial interaction with extracellular beta-amyloid fibrils (fAbeta) is mediated through an ensemble of cell surface receptors, including the B-class scavenger receptor CD36, the alpha(6)beta(1)-integrin, and the integrin-associated protein/CD47. The binding of fAbeta to this receptor complex has been shown to drive a tyrosine kinase-based signaling cascade leading to production of reactive oxygen species and stimulation of phagocytic activity; however, little is known about the intracellular signaling cascades governing the microglial response to fAbeta. This study reports a direct mechanistic link between the fAbeta cell surface receptor complex and downstream signaling events responsible for NADPH oxidase activation and phagosome formation. The Vav guanine nucleotide exchange factor is tyrosine-phosphorylated in response to fAbeta peptides as a result of the engagement of the microglia fAbeta cell surface receptor complex. Co-immunoprecipitation studies demonstrate an Abeta-dependent association between Vav and both Lyn and Syk kinases. The downstream target of Vav, the small GTPase Rac1, is GTP-loaded in an Abeta-dependent manner. Rac1 is both an essential component of the NADPH oxidase and a critical regulator of microglial phagocytosis. The direct role of Vav in fAbeta-stimulated intracellular signaling cascades was established using primary microglia obtained from Vav(-/-) mice. Stimulation of Vav(-/-) microglia with fAbeta failed to generate NADPH oxidase-derived reactive oxygen species and displayed a dramatically attenuated phagocytic response. These findings directly link Vav phosphorylation to the Abeta-receptor complex and demonstrate that Vav activity is required for fAbeta-stimulated intracellular signaling events upstream of reactive oxygen species production and phagosome formation.
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PMID:Fibrillar beta-amyloid-stimulated intracellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and microglia. 1672

Activation of the non-phagocytic superoxide-producing NADPH oxidase Nox1, complexed with p22(phox) at the membrane, requires its regulatory soluble proteins Noxo1 and Noxa1. However, the role of the small GTPase Rac remained to be clarified. Here we show that Rac directly participates in Nox1 activation via interacting with Noxa1. Electropermeabilized HeLa cells, ectopically expressing Nox1, Noxo1, and Noxa1, produce superoxide in a GTP-dependent manner, which is abrogated by expression of a mutant Noxa1(R103E), defective in Rac binding. Superoxide production in Nox1-expressing HeLa and Caco-2 cells is decreased by depletion or sequestration of Rac; on the other hand, it is enhanced by expression of the constitutively active Rac1(Q61L), but not by that of a mutant Rac1 with the A27K substitution, deficient in binding to Noxa1. We also demonstrate that Nox1 activation requires membrane recruitment of Noxa1, which is normally mediated via Noxa1 binding to Noxo1, a protein tethered to the Nox1 partner p22(phox): the Noxa1-Noxo1 and Noxo1-p22(phox) interactions are both essential for Nox1 activity. Rac likely facilitates the membrane localization of Noxa1: although Noxa1(W436R), defective in Noxo1 binding, neither associates with the membrane nor activates Nox1, the effects of the W436R substitution are restored by expression of Rac1(Q61L). The Rac-Noxa1 interaction also serves at a step different from the Noxa1 localization, because the binding-defective Noxa1(R103E), albeit targeted to the membrane, does not support superoxide production by Nox1. Furthermore, a mutant Noxa1 carrying the substitution of Ala for Val-205 in the activation domain, which is expected to undergo a conformational change upon Rac binding, fully localizes to the membrane but fails to activate Nox1.
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PMID:Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1. 1676 23

Statins have recently been shown to exert neuronal protection in ischemic stroke. Reactive oxygen species, specifically superoxide formed during the early phase of reperfusion, augment neuronal injury. NADPH oxidase is a key enzyme for superoxide production. The present study tested the hypothesis that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia. Transient focal ischemia was created in halothane-anesthetized adult male Sprague-Dawley rats (250-300 g) by middle cerebral artery occlusion (MCAO). Atorvastatin (Lipitor, 10 mg/kg sc) was administered three times before MCAO. Infarct volume was measured by triphenyltetrazolium chloride staining. NADPH oxidase enzymatic activity and superoxide levels were quantified in the ischemic core and penumbral regions by lucigenin (5 microM)-enhanced chemiluminescence. Expression of NADPH oxidase membrane subunit gp91(phox) and membrane-translocated subunit p47(phox) and small GTPase Rac-1 was analyzed by Western blot. NADPH oxidase activity and superoxide levels increased after reperfusion and peaked within 2 h of reperfusion in the penumbra, but not in the ischemic core, in MCAO rats. Atorvastatin pretreatment prevented these increases, blunted expression of membrane subunit gp91(phox), and prevented translocation of cytoplasmic subunit p47(phox) to the membrane in the penumbra 2 h after reperfusion. Consequently, cerebral infarct volume was significantly reduced in atorvastatin-treated compared with nontreated MCAO rats 24 h after reperfusion. These results indicate that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia.
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PMID:Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. 1676 36

Neutrophils produce microbicidal oxidants to destroy the invading pathogens using nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a membrane-associated enzyme complex that generates superoxide anion (O(2)(-)). Upon stimulation, the cytosolic components of NADPH oxidase, p47(phox) and p67(phox) and the small GTPase Rac move to phagosomal and plasma membranes where they become associated with the membrane components of NADPH oxidase, gp91(phox) and p22(phox) and express enzyme activity. We previously showed that taurine chloramine (Tau-Cl) inhibits O(2)(-) production in mouse peritoneal neutrophils (Kim, 1996). In the present study, we investigated the mechanisms underlying Tau-Cl-derived inhibition on O(2)(-) production using a human myeloid leukemia cell line, PLB-985 cell, which has been differentiated into neutrophil-like cell. Tau-Cl inhibited the phorbol myristate acetate (PMA)-elicited O(2)(-) production as previously observed in murine peritoneal neutrophils. Translocation of p47(phox), p67(phox) and Rac was increased in response to PMA, and Tau-Cl inhibited the PMA-stimulated translocation of p47(phox) and p67(phox) to plasma membrane without affecting the translocation of Rac. In addition, Tau-Cl inhibited the PMA-derived phosphorylation of p47(phox), a requirement for the translocation of cytosolic NADPH oxidase component to the plasma membrane. These results suggest that Tau-Cl inhibits PMA-elicited O(2)(-) production in PLB-985 granulocytes by inhibiting phosphorylation of p47(phox) and translocation of p47(phox) and p67(phox), eventually blocking the assembly of NADPH oxidase complex.
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PMID:Taurine chloramine inhibits PMA-stimulated superoxide production in human neutrophils perhaps by inhibiting phosphorylation and translocation of p47(phox). 1684 37

Deliberate production of reactive oxygen species (ROS) are catalyzed by enzymes that belong to the NAD(P)H oxidase (Nox) family. The human genome contains seven members of the Nox family: the superoxide-producing enzymes Nox1 through Nox5 and the dual oxidases Duox1 and Duox2 that release hydrogen peroxide but not superoxide. Among them, the classical member gp91( phox )/Nox2 functions as the phagocyte NADPH oxidase, playing a crucial role in host defense. Although Nox2, heterodimerized with its membrane-spanning partner p22( phox ), is inactive in resting cells, during phagocytosis it forms an active complex with soluble regulatory proteins such as the organizer p47( phox ), the activator p67( phox ), and the small GTPase Rac. Here the authors describe how the novel superoxide-producing Nox oxidases (Nox1, 3, 4, and 5) with different functions are regulated by p22( phox ), the Nox organizers, the Nox activators, and Rac, and how their expression is controlled at the transcriptional level.
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PMID:Regulation of novel superoxide-producing NAD(P)H oxidases. 1698 8

Generation of reactive oxygen species (ROS) can occur upon agonist stimulation of surface receptors to modulate downstream signaling processes. Here, we show that activation of the beta2 adrenergic receptor (beta2AR) by stimulation with the agonist isoproterenol leads to generation of ROS that is required for beta2AR signal transduction. Specifically, we show that inhibition of NADPH oxidase with diphenyliodonium chloride, inhibition of the small GTPase Rac1 with NSC23766, and inhibition of formed ROS with the antioxidant N-acetyl-L-cysteine decreases beta2AR-mediated cAMP formation, protein kinase A activation, and receptor phosphorylation and internalization, but does not impact ligand binding. The results also show that inhibition of ROS attenuates active beta2AR-mediated binding of GTP to alpha subunits of heterotrimeric G proteins. Based on these results, we propose that agonist-dependent ROS formation is needed for beta2AR signal transduction, perhaps through stabilization of active receptor conformers by redox-mediated modification of receptor and/or Galpha proteins cysteine residues.
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PMID:Agonist-stimulated reactive oxygen species formation regulates beta2-adrenergic receptor signal transduction. 1745 56


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