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:1.1.1.49 (glucose-6-phosphate dehydrogenase)
7,794 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A developmental block is induced by phosphate in rat embryos at the late two-cell stage. The present study was designed to examine the energy metabolism of rat two-cell blocked and non-blocked embryos. Enzyme activity was measured in individual embryos by histochemical techniques. The activities of malate dehydrogenase, isocitrate dehydrogenase, lactate dehydrogenase, pyruvate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, glutamate dehydrogenase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, and phosphorylase did not differ among non-blocked and blocked embryos. However, the activity of succinate dehydrogenase was significantly decreased in blocked embryos compared with non-blocked embryos. In blocked embryos, cytochrome oxidase activity was distributed homogeneously, but was located at the perinuclear region in non-blocked embryos. Active mitochondrial organization was visualized using the fluorescent probe rhodamine 123 and laser scanning confocal microscopy. In both non-blocked and blocked embryos, mitochondria were distributed homogeneously. The concentration of H2O2 measured fluorometrically in embryos cultured without phosphate did not change significantly during the culture period, but decreased in embryos cultured with phosphate. The timing corresponded to the occurrence of the two-cell block. In summary, these results suggest that the developmental block in rat two-cell embryos is induced by disturbance of mitochondrial energy metabolism.
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PMID:Microscopic analysis of enzyme activity, mitochondrial distribution and hydrogen peroxide in two-cell rat embryos. 986 Nov 63

Growth of Saccharomyces cerevisiae with a fatty acid as carbon source was shown previously to require function of either glucose-6-phosphate dehydrogenase (ZWF1) or cytosolic NADP+-specific isocitrate dehydrogenase (IDP2), suggesting dependence of beta-oxidation on a cytosolic source of NADPH. In this study, we find that DeltaIDP2DeltaZWF1 strains containing disruptions in genes encoding both enzymes exhibit a rapid loss of viability when transferred to medium containing oleate as the carbon source. This loss of viability is not observed following transfer of a DeltaIDP3 strain lacking peroxisomal isocitrate dehydrogenase to medium with docosahexaenoate, a nonpermissive carbon source that requires function of IDP3 for beta-oxidation. This suggests that the fatty acid- phenotype of DeltaIDP2DeltaZWF1 strains is not a simple defect in utilization. Instead, we propose that the common function shared by IDP2 and ZWF1 is maintenance of significant levels of NADPH for enzymatic removal of the hydrogen peroxide generated in the first step of peroxisomal beta-oxidation in yeast and that inadequate levels of the reduced form of the cofactor can produce lethality. This proposal is supported by the finding that the sensitivity to exogenous hydrogen peroxide previously reported for DeltaZWF1 mutant strains is less pronounced when analyses are conducted with a nonfermentable carbon source, a condition associated with elevated expression of IDP2. Under those conditions, similar slow growth phenotypes are observed for DeltaZWF1 and DeltaIDP2 strains, and co-disruption of both genes dramatically exacerbates the H2O2s phenotype. Collectively, these results suggest that IDP2, when expressed, and ZWF1 have critical overlapping functions in provision of reducing equivalents for defense against endogenous or exogenous sources of H2O2.
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PMID:Dependence of peroxisomal beta-oxidation on cytosolic sources of NADPH. 992 Aug 83

The protective activity of small stress proteins (sHsp) against H2O2-mediated cell death in the highly sensitive murine L929 fibroblast has been analyzed. We report here that the human Hsp27- and murine Hsp25-mediated rise in glutathione (GSH) levels as well as the maintenance of this redox modulator in its reduced form was directly responsible for the protection observed at the level of cell morphology and mitochondrial membrane potential. sHsp expression also buffered the increase in protein oxidation following H2O2 treatment and protected several key enzymes against inactivation. In this case, however, the protection necessitated both an increase in GSH and the presence of sHsp per se since the pattern of protection against protein oxidation mediated by a simple GSH increase was different from that induced by sHsp expression. Among the enzymes analyzed, we noticed that sHsp significantly increased glucose-6-phosphate dehydrogenase (G6PD) activity and to a lesser extent glutathione reductase and glutathione transferase activities. Moreover, an increased GSH level was observed in G6PD-overexpressing L929 cell clones. Taken together our results suggest that sHsp protect against oxidative stress through a G6PD-dependent ability to increase and uphold GSH in its reduced form and by using this redox modulator as an essential parameter of their in vivo chaperone activity against oxidized proteins.
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PMID:Mammalian small stress proteins protect against oxidative stress through their ability to increase glucose-6-phosphate dehydrogenase activity and by maintaining optimal cellular detoxifying machinery. 1004 48

The toxic potency of three industrially used hydroxylamines was studied in human blood cells in vitro. The parent compound hydroxylamine and the O-ethyl derivative gave very similar results. Both compounds induced a high degree of methemoglobin formation and glutathione depletion. Cytotoxicity was visible as Heinz body formation and hemolysis. High levels of lipid peroxidation occurred, in this respect O-ethyl hydroxylamine was more active than hydroxylamine. In contrast H2O2 induced lipid peroxidation was lowered after O-ethyl hydroxylamine or hydroxylamine treatment, this is explained by the ferrohemoglobin dependence of H2O2 induced radical species formation. Glutathione S-transferase (GST) and NADPH methemoglobin reductase (NADPH-HbR) activities were also impaired, probably as a result of the radical stress occurring. The riboflavin availability was decreased. Other enzyme activities glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PDH), glucose phosphate isomerase and NADH methemoglobin reductase, were not or only slightly impaired by hydroxylamine or O-ethyl hydroxylamine treatment. A different scheme of reactivity was found for N,O-dimethyl hydroxylamine. This compound gave much less methemoglobin formation and no hemolysis or Heinz body formation at concentrations up to and including 7 mM. Lipid peroxidase induction was not detectable, but could be induced by subsequent H2O2 treatment. GST and NADPH-HbR activities and riboflavin availability were not decreased. On the other hand GR and G6PDH activities were inhibited. These results combined with literature data indicate the existence of two different routes of hematotoxicity induced by hydroxylamines. Hydroxylamine as well as O-alkylated derivatives primarily induce methemoglobin, a process involving radical formation. The radical stress occurring is probably responsible for most other effects. N-alkylated species like N,O-dimethyl hydroxylamine primarily lead to inhibition of the protective enzymes G6PDH and GR. Since these enzymes play a key role in the protection of erythrocytes against oxidative stress a risk of potentiation during mixed exposure does exist.
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PMID:Two mechanisms for toxic effects of hydroxylamines in human erythrocytes: involvement of free radicals and risk of potentiation. 1008 86

In order to investigate the effect of fat-rich diets on neutrophil functions, 21 day-aged rats were fed for 6 weeks with a control diet consisting of a regular laboratory rodent chow (4 per cent final fat content), a control diet supplied with soybean oil (15 per cent final fat content), or a control diet supplied with coconut oil (15 per cent final fat content). Glycogen-elicited peritoneal neutrophils from rats fed soybean and coconut oil-enriched diets presented a reduction in spontaneous and PMA-stimulated H2O2 generation relative to neutrophils from rats fed the control diet. The activity of superoxide dismutase, glutathione peroxidase and catalase did not change in animals fed fat-rich diets. In addition, the capacity to generate O2-, spontaneously or in response to PMA, did not change in neutrophils from animals fed fat-rich diets. Values attained matched those observed in animals fed the control diet, regardless of the method used to measure O2-, the superoxide dismutase-inhibitable reduction of cytochrome c or the lucigenin-dependent chemiluminescence. However, the initial rate of O2- generation both in resting neutrophils and in PMA-stimulated cells was significantly reduced when animals were fed with coconut or soybean oil-enriched diets due, at least in part, to a reduction in the activity of glucose-6-phosphate dehydrogenase. The concentration of thiobarbituric acid reactive substances, an index of lipid peroxidation, was increased in animals fed both fat-rich diets. This was accompanied by an increase in arachidonic acid content in these cells. Results presented suggest that lipid peroxidation in neutrophils from animals fed fat-rich diets may be associated with a consumption of H2O2 yielding more reactive oxygen-derived species such as the hydroxyl radical.
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PMID:NADPH-oxidase activity and lipid peroxidation in neutrophils from rats fed fat-rich diets. 1019 9

The intracellular redox potential plays an important role in cell survival. The principal intracellular reductant NADPH is mainly produced by the pentose phosphate pathway by glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme, and by 6-phosphogluconate dehydrogenase. Considering the importance of NADPH, we hypothesized that G6PDH plays a critical role in cell death. Our results show that 1) G6PDH inhibitors potentiated H2O2-induced cell death; 2) overexpression of G6PDH increased resistance to H2O2-induced cell death; 3) serum deprivation, a stimulator of cell death, was associated with decreased G6PDH activity and resulted in elevated reactive oxygen species (ROS); 4) additions of substrates for G6PDH to serum-deprived cells almost completely abrogated the serum deprivation-induced rise in ROS; 5) consequences of G6PDH inhibition included a significant increase in apoptosis, loss of protein thiols, and degradation of G6PDH; and 6) G6PDH inhibition caused changes in mitogen-activated protein kinase phosphorylation that were similar to the changes seen with H2O2. We conclude that G6PDH plays a critical role in cell death by affecting the redox potential.
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PMID:Importance of glucose-6-phosphate dehydrogenase activity in cell death. 1032 61

In order to assess the integrity of antioxidant enzymes in Alzheimer's disease, the activities of glutathione peroxidase, glutathione reductase and two enzymes of the pentose phosphate pathway (glucose-6-phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase) were determined in three regions of postmortem neocortex of controls and subjects with Alzheimer's disease. The activities of glutathione peroxidase and glutathione reductase were unaffected in Alzheimer's disease. By contrast, there was a selective increase in the activities of glucose-6-phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase in the inferior temporal cortex of Alzheimer subjects. These changes negatively correlated with the Fe2+/ascorbate-induced lipid peroxidation which (in a previous study of the same subjects) was also found to be selectively elevated in the inferior temporal cortex. Increased activity of the pentose phosphate pathway probably occurs in response to increased prooxidant activity since both glucose-6-phosphate and 6-phosphonogluconate inhibited H2O2-induced lipid peroxidation in a concentration dependant fashion (IC50 = 504 +/- 105 microM and 88 +/- 12 microM, respectively). Together, these data suggest that not only is oxidative stress a feature of Alzheimer's disease, but also that it occurs because of increased prooxidant activity rather than a diminished antioxidant capacity.
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PMID:The activity of the pentose phosphate pathway is increased in response to oxidative stress in Alzheimer's disease. 1039 40

Sensitivity to various oxidants was determined for Escherichia coli strains JTG10 and 821 deficient in biosynthesis of glutathione (gsh-) and their common parental strain AB1157 (gsh+). The three strains showed identical sensitivity to H2O2. E. coli 821 was more resistant than AB1157 and JTG10 to menadione, cumene hydroperoxide, and N-ethylmaleimide. This resistance was not related to the gsh mutation because the other gsh- mutant and the parental strain showed similar sensitivity to these oxidants. The measured activities of NADPH:menadione diaphorase and glucose-6-phosphate dehydrogenase and the extracellular level of menadione suggested that the enhanced resistance of E. coli 821 to menadione might be due to decreased diaphorase activity, but not to a lowered rate of menadione uptake.
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PMID:Oxidative stress resistance of Escherichia coli strains deficient in glutathione biosynthesis. 1056 56

Nitric oxide (NO) shows cytotoxicity, and its reaction products with reactive oxygen species, such as peroxynitrite, are potentially more toxic. To examine the role of O2 in the NO toxicity, we have examined the proliferation of cultured human umbilical vein endothelial cells in the presence or absence of NO donor, ((Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-++ +ium-1,2-diolate) (DETA-NONOate) (100-500 microM), under normoxia (air), hypoxia (< 0.04% O2) or hyperoxia (88-94% O2). It was found that the dose dependency on NONOate was little affected by the ambient O2 concentration, showing no apparent synergism between the two treatments. We have also examined the effects of exogenous NO under normoxia and hyperoxia on the cellular activities of antioxidant enzymes involved in the H2O2 elimination, since many of them are known to be inhibited by NO or peroxynitrite in vitro. Under normoxia DETA-NONOate (500 microM) caused 25% decrease in catalase activity and 30% increases in glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities in 24h. Under hyperoxia NO caused about 25% decreases in activities of catalase, glutathione reductase and glucose-6-phosphate dehydrogenase. The H2O2 removal rate by NO-treated cells was computed on the mathematical model for the enzyme system. It was concluded that the cellular antioxidant function is little affected by NO under normoxia but that it is partially impaired when the cells are exposed to NO under hyperoxia.
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PMID:Interactions of nitric oxide and oxygen in cytotoxicity: proliferation and antioxidant enzyme activities of endothelial cells in culture. 1088 22

The anticancer activity of the hormonal form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], is associated with inhibition of cell cycle progression, induction of differentiation, and apoptosis. In addition, 1,25(OH)2D3 augments the activity of anticancer agents that induce excessive reactive oxygen species generation in their target cells. This study aimed to find out whether 1,25(OH)2D3, acting as a single agent, is a prooxidant in cancer cells. The ratio between oxidized and reduced glulathione and the oxidation-dependent inactivation of glyceraldehyde-3phosphate dehydrogenase (GAPDH) are considered independent markers of cellular reactive oxygen species homeostasis and redox state. Treatment of MCF-7 breast cancer cells with 1,25(OH)2D3 (10-100 nM for 24-48 h) brought about a maximal increase of 41+/-13% (mean +/- SE) in the oxidized/reduced glutathione ratio without affecting total glutathione levels. The in situ activity of glutathione peroxidase and catalase were not affected by 1,25(OH)2D3, as assessed by the rate of H2O2 degradation by MCF-7 cell cultures. Neither did treatment with 1,25(OH)2D3 affect the levels of glutathione reductase or glutathione S-transferase as assayed in cell extracts. The hormone did not affect overall glutathione consumption and efflux as reflected in the rate of decline of total cellular glutathione after inhibition of its synthesis by buthionine sulfoximine. The extent of reversible oxidation-dependent inactivation of GAPDH in situ was determined by comparing the enzyme activity before and after reduction of cell extracts with DTT. The oxidized fraction was 0.13+/-0.02 of total GAPDH in control cultures and increased by 56+/-5.3% after treatment with 1,25(OH)2D3, which did not affect the total reduced enzyme activity. Treatment with 1,25(OH)2D3 resulted in a approximately 40% increase in glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the generation of NADPH. This enzyme is induced in response to various modes of oxidative challenge in mammalian cells. Taken together, these findings indicate that 1,25(OH)2D3 causes an increase in the overall cellular redox potential that could translate into modulation of redox-sensitive enzymes and transcription factors that regulate cell cycle progression, differentiation, and apoptosis.
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PMID:Vitamin D is a prooxidant in breast cancer cells. 1124 48


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