Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.6 (NADPH oxidase)
 10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary immunodeficiencies are attractive candidates for the development of gene therapy approaches based on the transduction of hematopoietic cells. We have constructed a high-titer recombinant retrovirus for expression of gp91-phox, deficiencies of which cause the X-linked form of chronic granulomatous disease (X-CGD). We have used this vector to transduce human bone marrow, using either unfractionated mononuclear cells or purified CD34+ cells as targets and evaluated several infection protocols. Efficient gene transfer to progenitors and long-term culture-initiating cells (LTC-IC) was obtained for each target population. Importantly for potential clinical application, this could be achieved without the use of exogenous cytokines or polybrene. Progenitors representing each of the lineages detectable in vitro were transduced at equal efficiencies. The vector was shown partially to restore gp91-phox deficiency and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in transduced cells derived from X-CGD patients. These data demonstrate that it is possible to transduce primitive human hematopoietic cells efficiently and reconstitute NADPH oxidase.
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PMID:Efficient retroviral transduction of human bone marrow progenitor and long-term culture-initiating cells: partial reconstitution of cells from patients with X-linked chronic granulomatous disease by gp91-phox expression. 861 97

NADPH oxidase cytochrome b558 consists of two subunits, gp91-phox and p22-phox, defects of which result in chronic granulomatous disease (CGD). The nature of the interaction between these subunits has yet to be determined. Absence of p22-phox in autosomal CGD patient-derived B-cell lines results in detectable levels of an incompletely glycosylated gp91-phox precursor. We have detected this same precursor species in four cell lines from patients with the X-linked form of the disease due to mutations in gp91-phox. Such mutations should delineate regions of gp91-phox important for its biosynthesis, including stable association with p22-phox. One mutation mapped to the putative FAD-binding domain, one mapped to a potential haem-binding domain, and two involved the region encoded by exon 3.
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PMID:Detection of gp91-phox precursor protein in B-cell lines from patients with X-linked chronic granulomatous disease as an indicator for mutations impairing cytochrome b558 biosynthesis. 861 31

Mice with chronic granulomatous disease (X-CGD mice) generated by mutating the X-linked gene for a subunit of NADPH oxidase have been analyzed for their ability to respond to intravenous injection of purified cobra venom factor (CVF). This agent in wild-type mice produces a neutrophil-dependent and catalase-sensitive form of lung injury. Lung injury was evaluated by measuring the accumulation of extravascular albumin. Quite unexpectedly, the lungs of X-CGD mice showed no difference in the increased accumulation of extravascular albumin after injection of CVF when compared to wild-type mice. In both X-CGD and wild-type mice, full development of injury required neutrophils. While catalase was highly protective in wild-type mice, its protective effects were completely lost in the X-CGD mice. Furthermore, a competitive antagonist of L-arginine, N(G)-methyl-L-arginine, was protective in X-CGD mice but not in wild-type mice. Allopurinol was protective in both types of mice. Both the basal and the CVF-inducible lung mRNA for inducible nitric oxide synthase and IL-1beta was similar in X-CGD and wild-type mice. These data indicate that oxygen radical production and lung injury in response to injection of CVF occurs through alternative pathways in mice with genetic deletion of NADPH oxidase.
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PMID:Preservation of complement-induced lung injury in mice with deficiency of NADPH oxidase. 864 63

We have identified a rare polymorphism (G to C at nucleotide 1102) in CYBB, which codes for gp91-phox, a component of NADPH oxidase. Polymorphonuclear leukocytes with this enzyme produced normal amounts of superoxide anion.
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PMID:A novel polymorphism in the coding region of CYBB, the human gp91-phox gene. 865 40

The feasibility of correction of the disease phenotype by gene gene transfer was investigated in cells of four patients with X-linked chronic granulomatous disease. These patients carry point mutations of the gp91-phox gene, encoding for the large subunit of the catalytic core of the phagocytic cell NADPH oxidase. A retroviral vector expressing the gp91-phox protein was constructed and used to transduce lymphoblastoid cell lines established from the patients. Several transduced lymphoblastoid cell clones were investigated for mRNA and protein expression, and for functional reconstitution of oxidase activity. Although extensive quantitative variability was detected among different clones, functional reconstitution of O2- production was obtained in most cases, with oxidase function within the same range as in B cell lines derived from normal individuals. The same vector was also used for transduction of hematopoietic precursors from bone marrow or peripheral blood either with or without enrichment for CD34+ cells. A comprehensive analysis was performed on differentiated myeloid colonies, to evaluate the efficiency of transduction, the levels of gp91-phox expression, and the extent of functional reconstitution of oxidase activity. A high efficiency of transduction was obtained in most experiments, with 60-100% of colonies containing proviral DNA. Among the transduced colonies, an extensive variability in the levels of expression of the transduced gene and of functional restoration of NADPH oxidase activity was observed. These results represent a step toward the development of a gene therapy protocol for these patients.
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PMID:Functional reconstitution of oxidase activity in X-linked chronic granulomatous disease by retrovirus-mediated gene transfer. 866 Sep 13

The yeast two-hybrid system is finding increased use in the study of interactions between proteins. In this method, two polypeptides are expressed in yeast as fusion proteins to a transcriptional activator DNA-binding domain (bd) and activating domain (ad), respectively. Interaction between the two polypeptides reconstitutes function of a transactivator which controls expression of reporters. The phagocyte NADPH oxidase is a complex of membrane cytochrome b558 (comprised of subunits p22-phox and gp91-phox) and three cytosol proteins (p47-phox, p67-phox, and p21rac) that translocate to membrane and bind to cytochrome b558. This is the first report to demonstrate that two of cytosolic components of cytochrome b558, p47-phox binding to p67-phox each other. We encountered several methodological problems in the two-hybrid system which are the focus of this report.
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PMID:Elimination of false negative results in the two-hybrid system in the phagocyte NADPH oxidase. 867 37

The human NADPH oxidase is a very intriguing enzyme; although its catalytic unit is retained within cytochrome b558, various additional proteins are required for activity of the NADPH oxidase. In the past few years substantial progress has been made to elucidate the protein-protein interactions and the activation events involved. The following facts have become evident: (1) activation of rac and subsequent interaction with p67-phox is crucial for the interaction of p67-phox with cytochrome b558, and probably with gp91-phox; (2) p47-phox interacts with p22-phox, and phosphorylation of 379Ser of p47-phox is obligatory for this event; (3) p47-phox and p67-phox regulate each other's translocation in a positive sense (see also reference 71). To put it differently: it is vital to gain insight in the intrigues within the phox family and associated characters to fully understand NADPH oxidase activation.
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PMID:Interactions between the components of the human NADPH oxidase: intrigues in the phox family. 890 Feb 89

A 10-month-old Japanese male infant, with no history of being prone to infections, contracted an intrapulmonary mycobacterial infection. After 2 months of intermittent fever, radiological examinations revealed mass lesions in the lung and mediastinum. Biopsy specimens showed granulomas with caseous necrosis, from which Mycobacterium avium was isolated. There was no history of mycobacteriosis or immunodeficiency diseases among his relatives. Analyses of the O2- release and expression of NADPH oxidase components verified that he suffered from gp91-phox- chronic granulomatous disease (CGD), and that his mother was a carrier of the disease. This is a rare clinical presentation for the onset of CGD, suggesting that the invasive mycobacteriosis might result from defective intracellular killing of CGD-phagocytes.
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PMID:Intrapulmonary Mycobacterium avium infection as the first manifestation of chronic granulomatous disease. 913 39

When microorganisms invade the body, they encounter a large asssortment of defense mechanisms. Among these, phagocytes play an important role in the process of killing pathogens. This event is mediated by two important processes, viz. activation of the NADPH oxidase enzyme, which leads to the production of toxic oxygen metabolites, and fusion of intracellular granules with the phagosome (the vesicle that contains the ingested micro-organisms), which causes release of the toxic granule contents into this vesicle. The human NADPH oxidase is a very complex enzyme, in two ways: 1. it exists of at least 6 components: cytochrome b558 (a heterodimer comprised of gp91-phox and p22-phox), p47-phox, p67-phox, p40-phox, rac and Rap1A, and 2. there are multiple signal transduction pathways leading to activation of the NADPH oxidase. The most likely reason for this complexity is the toxicity of the oxygen radicals produced by the active NADPH oxidase; these compounds are not only harmful to the invading pathogens, but also to the surrounding tissues. This latter effect is enforced by the activation of metalloproteases released by neutrophils and by oxidation of protease inhibitors by oxygen metabolites. Therefore, an improper activation of the NADPH oxidase must be prevented at all costs and, when the infection has been cleared, a rapid deactivation mechanism is imperative. In this review, the interaction between the different components of the NADPH oxidase and the activation of these proteins will be discussed.
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PMID:Interactions between the components of the human NADPH oxidase: a review about the intrigues in the phox family. 915 14

The generation of superoxide by the NADPH oxidase of neutrophils is accompanied by the efflux of H+ ions through a H+ channel. gp91-phox, a protein component of the oxidase, has been shown previously to function as a H+ channel [Henderson, Banting and Chappell (1995) J. Biol. Chem. 270, 5909-5916]. We have constructed a CHO cell line (CHO-N) that expresses an N-terminal fragment of gp91-phox containing the predicted multiple transmembrane domains of the protein. These cells exhibit H+ fluxes in response to an imposed proton motive force and in the presence of arachidonate (to open the channel). The H+ fluxes were indistinguishable from those observed in cells expressing full-length gp91-phox. Therefore the N-terminal 230 amino acids of gp91-phox contain all that is required to function as the NADPH oxidase-associated H+ channel.
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PMID:The arachidonate-activatable, NADPH oxidase-associated H+ channel is contained within the multi-membrane-spanning N-terminal region of gp91-phox. 927 Oct 91


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