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)

Endothelial thrombomodulin (TM) plays a critical role in hemostasis as a cofactor for thrombin-dependent formation of activated protein C, a potent anticoagulant. Chloramine T, H2O2, or hypochlorous acid generated from H2O2 by myeloperoxidase rapidly destroy 75-90% of TM cofactor activity. Activated PMN, the primary in vivo source of biological oxidants, also rapidly inactivate TM. Oxidation of TM by PMN is inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase. Both Met291 and Met388 in the six epidermal growth factor-like repeat domain are oxidized; however, only substitutions of Met388 lead to TM analogues that resist oxidative inactivation. We suggest that in inflamed tissues activated PMN may inactivate TM and demonstrate further evidence of the interaction between the inflammatory process and induction of thrombotic potential.
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PMID:Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation. 133 78

Chronic granulomatous disease (CGD) is an inherited group of disorders in which phagocytic leukocytes (neutrophils, eosinophils, monocytes, and macrophages) fail to undergo a respiratory burst when stimulated. The products of the respiratory burst, which include superoxide and hypochlorous acid, play a critical role in killing pathogenic bacteria, fungi, and parasites. As a result of the failure to activate the respiratory burst in their phagocytes, most CGD patients suffer from severe recurrent infections. While all CGD patients share this severe defect, there is substantial heterogeneity in the molecular mechanisms responsible. The enzyme that catalyzes the respiratory burst, NADPH oxidase, has been extensively characterized and found to consist of at least four subunits: gp91-phox and p22-phox (the two subunits of a low potential cytochrome b that is the terminal electron carrier of the oxidase) as well as p47-phox and p67-phox (two cytosolic oxidase components). CGD is caused by a defect in any one of these four components, thus explaining the previously confusing genetic heterogeneity of this disorder. In approximately thirty reported cases, the underlying mutations involving these oxidase components have been identified. The current understanding of the molecular basis of CGD is reviewed in the context of a recently completed Phase III clinical trial establishing the efficacy of recombinant human interferon gamma in the treatment of CGD.
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PMID:Molecular basis of the autosomal recessive forms of chronic granulomatous disease. 155 99

Evidence strongly suggests that many adverse drug reactions, including idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to reactive metabolites, are associated with a high incidence of adverse reactions. Most drugs can probably form reactive metabolites, but a simple comparison of covalent binding in vitro is unlikely to provide an accurate indication of the relative risk of a drug causing an idiosyncratic reaction because it does not provide an indication of how efficiently the metabolite is detoxified in vivo. In addition, the incidence and nature of adverse reactions associated with a given drug is probably determined in large measure by the location of reactive metabolite formation, as well as the chemical reactivity of the reactive metabolite. Such factors will determine which macromolecules the metabolites will bind to, and it is known that covalent binding to some proteins, such as those in the leukocyte membrane, is much more likely to lead to an immune-mediated reaction or other type of toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely and could lead to adverse reactions in almost any organ; however, most reactive metabolites have a short biological half-life, and although small amounts may escape the organ where they are formed, these metabolites are unlikely to reach sufficient concentrations to cause toxicity in other organs. Many idiosyncratic drug reactions involve leukocytes, especially agranulocytosis and drug-induced lupus. We and others have demonstrated that drugs can be metabolized by activated neutrophils and monocytes to reactive metabolites. The major reaction appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous acid is quite reactive, and therefore it is likely that many other drugs will be found that are metabolized by activated leukocytes. Some neutrophil precursors contain myeloperoxidase and the NADPH oxidase system, and it is likely that these cells can also oxidize drugs. Therefore, although there is no direct evidence, it is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia. This could involve direct toxicity or an immune-mediated reaction. These mechanisms are not mutually exclusive, and it may be that both mechanisms contribute to the toxicity, even in the same patient. In the case of drug-induced lupus, a prevalent hypothesis for lupus involves modification of class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. 162 36

Phagocytic leukocytes generate large amounts of reactive oxygen compounds during and after phagocytosis of micro-organisms. These compounds are essential for the killing of a wide variety of microbes. The enzyme responsible for this process is NADPH:O2 oxidoreductase (NADPH oxidase), which utilizes the reduction equivalents of NADPH to reduce atmospheric oxygen to superoxide (O2-.). Subsequently, superoxide is converted by the leukocytes to other reactive compounds, such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and N-chloramines (RNCl). Each of these compounds has potent microbicidal properties. Under resting, non-phagocytizing conditions, phagocytes do not produce reactive oxygen compounds. However, within 15-30 sec after binding of micro-organisms to cell surface receptors, superoxide generation starts. This phenomenon is called the respiratory burst. This phenomenon is called the respiratory burst. The activation of the NADPH oxidase is caused by the assembly of components of this enzyme into an active complex. Under resting conditions, at least three components reside in the cytoplasm and at least two are located in the plasma membrane. Activation of the NADPH oxidase results in translocation of cytosolic components to the plasma membrane and formation of an active enzymatic complex in the plasma membrane.
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PMID:The involvement of oxygen radicals in microbicidal mechanisms of leukocytes and macrophages. 179 94

Generation of reactive oxygen species is a critical event in successful host defense against invading organisms. Work spanning at least 25 years has demonstrated that both neutrophils and macrophages rely on a variety of oxidants to damage bacterial constitutents. The neutrophil is armed with two different oxygen-dependent defenses, while the macrophage relies solely on nonenzymatic oxidant generation. The primary granules of neutrophils contain the enzyme myeloperoxidase, which combines with H2O2 and ultimately leads to production of many toxic oxidant species: Halogens, hypochlorous acid, chloramines, aldehydes, and singlet oxygen. All of these molecules are involved in potentially toxic structural alterations in the pathogen. MPO-independent oxidant generation in neutrophils and macrophages involves the generation of highly toxic species derived from the interaction of O2- and H2O2, such as hydroxyl radical and singlet oxygen. Recent work has concentrated on determining how the interaction of a phagocyte with a foreign particle ultimately triggers the oxidant cascade. Exciting work in the past several years has focused on the proposal that protein kinase C and intracellular Ca2+ are two important focal points, and the activation of these two species leads to NADPH oxidase activation and subsequent conversion of O2 to O2-. The exact mechanism coupling stimulus binding to response promises to be an exciting area of research in the years to come.
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PMID:The role of the respiratory burst of phagocytes in host defense. 282 13

Polymorphonuclear neutrophilic leukocytes (PMNs) take up opsonized microorganisms into phagosomes that fuse with secretory granules in the PMN cytoplasm to form phagolysosomes. Killing and digestion of microorganisms take place within phagolysosomes. Antimicrobial activities in phagolysosomes are divided into two classes. Oxygen (O2)-dependent mechanisms are expressed when PMNs undergo the "respiratory burst." An NADPH oxidase in the phagolysosome membrane is activated and reduces O2 to superoxide (O2-). O2 reduction is the first step in a series of reactions that produce toxic oxidants. For example, .O2- dismutases to hydrogen peroxide (H2O2), and the azurophil granule enzyme myeloperoxidase catalyzes the oxidation of Cl- by H2O2 to yield hypochlorous acid (HOCl). The reaction of HOCl with ammonia and amines modulates the toxicity of this oxidant. O2-independent antimicrobial mechanisms include the activities of lysosomal proteases, other hydrolytic enzymes, and proteins and peptides that bind to microorganisms and disrupt essential processes or structural components. For example, the bactericidal/permeability-increasing protein, cathepsin G, and the defensins are released into phagolysosomes from the azurophil granules. Proposed mechanisms of action of neutrophil antimicrobial agents, their range of microbial targets, and their possible interactions within phagolysosomes are discussed.
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PMID:Human neutrophil antimicrobial activity. 305 15

Diphenyleneiodonium (DPI), an inhibitor of the NADPH oxidase, has been used to distinguish between oxidative and nonoxidative killing of Staphylococcus aureus and Escherichia coli by neutrophils. The rate of killing of S. aureus was inhibited by 77% in the presence of 10 microM DPI, compared to 81% measured under anaerobic conditions. DPI represents a convenient and accessible alternative to an anaerobic environment or using neutrophils from patients with chronic granulomatous disease, for eliminating oxidative killing. The killing of E. coli was also inhibited by DPI. The effect was more apparent at 30 min than at 10 min, suggesting that E. coli can be killed rapidly by nonoxidative mechanisms that become less efficient at later times. DPI was used at concentrations less than 10 microM to determine how this affected production of the three major neutrophil oxidants, superoxide, hydrogen peroxide, and hypochlorous acid, and to determine the effect of partial inhibition of oxidant production on the killing of S. aureus. Unexpectedly, lower concentrations of DPI (0.1-2 microM) inhibited hydrogen peroxide and hypochlorous acid production 10-30% more than they inhibited superoxide production. Correlation of hydrogen peroxide or hypochlorous acid production with the killing of S. aureus showed that up to 30% inhibition had no effect on the rate of killing, implying that agents that impair neutrophil oxidant production less than this will not compromise bacterial killing. Higher inhibition of oxidant production led to a linear decline in the rate of killing.
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PMID:Modification of neutrophil oxidant production with diphenyleneiodonium and its effect on bacterial killing. 775 Jul 87

The release of proteolytic enzymes and generation of strong oxidants such as the hydroxyl radical by activated neutrophils has been proposed to play an important role in mediating toxin-induced liver injury. The antithyroid drug propylthiouracil protects against liver injury induced by many hepatotoxic agents and markedly reduces mortality in patients with alcoholic liver disease. However, the mechanism(s) by which propylthiouracil protects against liver injury is not well understood. The present studies investigate the effect of antithyroid drugs on proteolytic enzyme activity and on hydroxyl radical generation from activated neutrophils. In the presence of hydrogen peroxide and chloride, neutrophil myeloperoxidase, an enzyme from the same gene superfamily as thyroid peroxidase, generates hypochlorous acid which inactivates alpha-1-proteinase inhibitor (A1PI) present in serum. This inactivation allows neutrophil-released proteolytic enzymes to attack cells. In the present study myeloperoxidase activity was inhibited fully at therapeutic concentrations by antithyroid drugs (propylthiouracil and methimazole). Antithyroid drugs fully prevented hypochlorous acid formation, and prevented neutrophil-mediated inactivation of A1PI, with concomitant blockage of proteolytic activity. Conversely, generation of both superoxide and hydroxyl radicals by activated neutrophils was unaffected by propylthiouracil. The production of these oxygen radicals was fully inhibited by the NADPH oxidase inhibitor diphenylene iodonium chloride, however. These studies indicate that antithyroid drugs are unlikely to prevent cell injury by inhibiting hydroxyl radical generation or by scavenging hydroxyl radicals, but are likely to exert their hepatoprotective anti-inflammatory action by inhibiting neutrophil myeloperoxidase, an enzyme akin to thyroid peroxidase.
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PMID:Effect of antithyroid drugs on hydroxyl radical formation and alpha-1-proteinase inhibitor inactivation by neutrophils: therapeutic implications. 961 27

The role of the inflammatory cytokine interleukin 1beta (IL-1beta) as potent agonist of the PMN respiratory burst signal transduction cascade has been described. We hypothesized that this phenomenon is self-limiting and that polymorphonuclear leukocyte (PMN)-derived reactive oxygen intermediates (ROI) might provide feedback regulation on the IL-1beta surface receptor (IL-1betaR)-G-protein-effector enzyme transducing tripartite complex that ultimately leads to NADPH oxidase activation. Therefore, we separately assessed either baseline or IL-1beta-induced activation of each member of the IL-1betaR-G-protein-phospholipase D (PLD) or IL-1betaR-G-protein-phospholipase C (PLC) signaling systems in the presence or absence of one of several specific ROI scavengers/antioxidants. Purified human PMN were lipopolysaccharide primed, adhered for 2 h, and stimulated with 100 ng/mL IL-1beta with or without 1% v/v dimethyl sulfoxide, 10 mM NaN3, 30 mM L-alanine, 200 U catalase, or 300 U superoxide dismutase (SOD). To validate the use of these antioxidants, the production of O2-, H2O2, hypochlorous acid, or myeloperoxidase (MPO) in the employed experimental model was confirmed in a separate set of experiments. The expression of IL-1betaR type I or II was assessed by binding with corresponding 125I-labeled monoclonal antibodies and corrected for nonspecific binding. PLD activation was assessed by measuring phosphatidyl ethanol formation in the presence of ethanol. PLC activation was determined by quantitative measurement of diacylglycerol. The level of Galpha stimulatory and inhibitory subunits was assessed by Western blotting. IL-1betaR type I expression was significantly up-regulated in the presence of catalase and SOD. PLD activation was increased by dimethyl sulfoxide and NaN3, and PLC activation was up-regulated by NaN3, L-alanine, SOD, and catalase. After 5 min of stimulation with IL-1beta, Gialpha expression was significantly down-regulated by NaN3 and SOD, whereas SOD had an up-regulating effect on the expression of Gs alpha. Increasing concentrations of externally added authentic MPO progressively down-regulated both PLD and PLC activity. Thus, PMN-derived ROI, in addition to their role as antibacterial/fungal agents, serve as second messengers in IL-1beta signal transduction, with MPO having the most ubiquitous role as a modulator of PMN second messenger pathways.
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PMID:The role of neutrophil-derived oxidants as second messengers in interleukin 1beta-stimulated cells. 968 92

Chloride anions and hydrogen peroxide serve as substrates for myeloperoxidase (MPO) in order to produce hypochlorous acid (HOCl) as one of the major killing agents of phagocytic leukocytes. Apart from this role of being a substrate for the MPO-reaction the chloride anion has been considered as unreactive and has not been implicated in radical reactions which contribute to the killing process. From the inherent reactivities of the pertinent radicals (as determined by pulse radiolysis experiments), the great abundance of chloride, and the most probable distribution of reactants within the phagosome, we deduce estimates for the average life-time and free diffusion path-length in this milieu and arrive at a model according to which chloride ions enter into radical chains and influence the killing of ingested bacteria to an extraordinarily high extent. We propose that hydroxyl radicals--despite some controversial arguments in the literature--may still be considered as important contributors to cell killing especially since we show that their reactions are made more effective by producing chlorine radicals in a cyclic process. We furthermore present arguments how the phagocyte may protect itself from harmful actions of HOCl and H2O2 after the superoxide-generating activity of NADPH oxidase is turned off.
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PMID:Phagocytic killing of microorganisms by radical processes: consequences of the reaction of hydroxyl radicals with chloride yielding chlorine atoms. 989 41


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