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)

The influence of O2-, H2O2 and metal ions on the auto-oxidation of divicine, a pyrimidine aglycone, was studied. In air at pH 7.4, the hydroquinonic form oxidized within a few minutes. Superoxide dismutase (SOD) markedly decreased the initial rate, giving a lag phase followed by rapid oxidation. Although catalase or diethylenetriamine-penta-acetic acid (DTPA) alone had little effect, each in the presence of SOD further slowed the initial rate and increased the lag. H2O2 decreased the lag time, as did Cu2+, Fe2+ or haemoglobin. GSH substantially increased the lag phase, but it eventually reacted with the divicine to form a 305 nm-absorbing adduct. These results indicate that an O2(-)-dependent mechanism of divicine auto-oxidation normally predominates. Auto-oxidation can also occur by a mechanism involving H2O2 and transition metal ions or haemoglobin, and if both these reactions are prevented by SOD and DTPA or catalase, a third mechanism, requiring build-up of an autocatalytic intermediate, becomes operative. Oxyhaemoglobin did not react directly with divicine, but reacted with the H2O2 produced by divicine auto-oxidation to give mainly an oxidized derivative presumed to be ferrylhaemoglobin. Divicine was shown to reduce ferylhaemoglobin to methaemoglobin, and this reaction was probably responsible for the acceleratory effect of haemoglobin on divicine oxidation. These results indicate that O2 rather than oxyhaemoglobin is likely to initiate divicine oxidation in the erythrocyte. Haemolytic crises, which are thought to result from this oxidation, occur only sporadically in glucose-6-phosphate dehydrogenase deficient individuals following ingestion of fava beans. A characteristic of the crises is acute depletion of erythrocyte GSH, and the vulnerability of these cells could relate to the ability of GSH, in combination with SOD, to protect against the autocatalytic mechanism of divicine auto-oxidation. Our demonstration of a variety of auto-oxidation pathways also suggests possible areas of individual variation.
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PMID:Contributions of superoxide, hydrogen peroxide, and transition metal ions to auto-oxidation of the favism-inducing pyrimidine aglycone, divicine, and its reactions with haemoglobin. 301 7

Calpain, the micromolar Ca2+-requiring form of Ca2+-stimulated neutral proteinase purified from human red cells, is remarkably inactivated during autoxidation of divicine (2,6-diamino-4,5-dihydroxypyrimidine), an aglycone implicated in the pathogenesis of favism. Inactivation of purified calpain is produced, in decreasing order of efficiency, by transient, probably semiquinonic species arising from autoxidation of divicine, by the H2O2 that is formed upon autoxidation itself, and by quinonic divicine, respectively. Purified procalpain, the millimolar Ca2+-requiring form that can be converted to the fully active calpain form by a variety of mechanisms, is less susceptible than calpain itself to inactivation by the same by-products of divicine autoxidation. When intact red cells are exposed to autoxidizing divicine, procalpain undergoes a significant loss of activity. At 1 mM divicine, intracellular inactivation is observed with procalpain only, while the activity of a number of red cell enzymes is unaffected. Inactivation of procalpain is consistently greater in red cells from glucose-6-phosphate dehydrogenase-deficient subjects than in normal cells. Restoration of normal levels of glucose-6-phosphate dehydrogenase activity by means of entrapment of homogeneous human glucose-6-phosphate dehydrogenase in the deficient red cells results in normal stability of intracellular reduced glutathione; decreased susceptibility of procalpain to inactivation by autoxidizing divicine. These findings suggest that in the glucose-6-phosphate dehydrogenase-deficient red cells the procalpain-calpain system is a major target of divicine cytotoxicity.
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PMID:Oxidative inactivation of the calcium-stimulated neutral proteinase from human red blood cells by divicine and intracellular protection by reduced glutathione. 302 66

Interactions of human platelets with cadmium in vitro were studied with respect to the platelet activation process as indicated by malondialdehyde (MDA) formation and also to the components of the cellular antioxidant defence system such as catalase, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), glucose-6-phosphate dehydrogenase (G6PDH), and reduced glutathione (GSH). Cadmium treatment stimulated platelet MDA formation after a lag phase of at least 15 min and this effect was completely blocked by either 1 mM aspirin or 1 mM CaCl2. Cadmium pretreated platelets also displayed a much higher (5 fold) MDA formation when stimulated by thrombin. Platelet catalase activity was decreased by almost 50% after incubation with cadmium. There was also a moderate decline in platelet GSH and GR activity along with a stimulation of GST and G6PDH activity. These results suggest: (1) the cadmium effect on platelets as observed by enhanced formation of MDA via the cyclooxygenase pathway involves intraplatelet accumulation of cadmium which is inhibited by calcium, (2) a modest decline in GSH, presumably due to the inadequacy of H2O2 detoxification mechanism, does not adversely affect platelet function because of the adaptive response of G6PDH, and (3) intracellular accumulation of cadmium may result in platelet hyperactivity through higher intraplatelet free calcium levels resulting directly through cadmium action or indirectly through higher H2O2 levels due to catalase inhibition.
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PMID:Effects of cadmium treatment in vitro on the antioxidant protection mechanism and activation of human blood platelets. 313 42

Preexposure to hypoxia increased survival and lung reduced glutathione-to-oxidized glutathione ratios (GSH/GSSG) and decreased pleural effusions in rats subsequently exposed to continuous hyperoxia. In addition, lungs from hypoxia-preexposed rats developed less acute edematous injury (decreased lung weight gains and lung lavage albumin concentrations) than lungs from normoxia-preexposed rats when isolated and perfused with hydrogen peroxide (H2O2) generated by xanthine oxidase (XO) or glucose oxidase (GO). In contrast, when perfused with elastase or exposed to a hydrostatic left atrial pressure challenge, lungs isolated from hypoxia-preexposed rats developed the same acute edematous injury as lungs from normoxia-preexposed rats. The mechanism by which hypoxia preexposure conferred protection against H2O2 appeared to depend on hexose monophosphate shunt (HMPS)-dependent increases in lung glutathione redox cycle activity. First, before perfusion with GO, lungs from hypoxia-preexposed rats had increased glutathione peroxidase and glucose 6-phosphate dehydrogenase (but not catalase or glutathione reductase) activities compared with lungs from normoxia-preexposed rats. Second, after perfusion with GO, lungs from hypoxia-preexposed rats had increased H2O2 reducing equivalents, as reflected by increased GSH/GSSG and NADPH/NADPH+, compared with lungs from normoxia-preexposed rats. Third, pretreatment of rats with an HMPS inhibitor, (6-aminonicotinamide) or a glutathione reductase inhibitor, [1,3-bis(2-chloroethyl)-1-nitrosourea] prevented hypoxia-conferred protection against H2O2-mediated acute edematous injury in isolated lungs. These findings suggest that increased detoxification of H2O2 by glutathione redox cycle and HMPS-dependent mechanisms contributes to tolerance to hyperoxia and resistance to H2O2 of lungs from hypoxia-preexposed rats.
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PMID:Hypoxia increases glutathione redox cycle and protects rat lungs against oxidants. 321 62

Content of glucose as well as activities of glyceraldehyde phosphate dehydrogenase (alpha-GPD), glucose-6-phosphate dehydrogenase (G6PD), superoxide dismutase (SOD) and catalase were studied in whole blood, in intact and hemolyzed erythrocytes of 57 volunteers within 120 min after sucrose loading. Direct correlation was found between the activity of the enzymes studied and level of glucose as well as the rate of its utilization in erythrocytes. These data suggest that reduced NAD- and NADP-containing oxidoreductases alpha-GPD and G6PD are donors of H+ used in biosynthesis of H2O2 catalyzed by SOD. Intact and hemolyzed erythrocytes are involved in destruction of H2O2 accompanied by liberation of O2, which reacted with Hb more readily as compared with atmospheric oxygen.
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PMID:[Changes in glyceraldehydephosphate dehydrogenase, glucose-6-phosphate dehydrogenase, superoxide dismutase, and catalase activity in erythrocytes depending upon the rate of glucose utilization]. 321 46

Red blood cells (RBCs) from 15 normal human blood samples were incubated with different concentrations of hydrogen peroxide in sodium azide, and the effects of the peroxidation on several glycolytic and nucleotidic enzyme activities were investigated. The release of malonyl dialdehyde (MDA) and methemoglobin formation were used as indicators of RBC peroxidation. The increase of H2O2, final concentration from 0.1 to 5 mmol/l, resulted in a progressive rise of almost all glycolytic enzyme activities, especially those of aldolase (200% of normal at 1 mmol/l), phosphoglycerate kinase (140%), phosphoglycerate mutase (136%), pyruvate kinase (130%) and glutathione peroxidase (130%), and in a decrease of glucose-6-phosphate dehydrogenase (68%) and pyrimidine-5-nucleotidase (23%). The addition of beta-mercaptoethanol to the incubation medium abolished only the effect of 1 mmol/l H2O2 on glucose-6-phosphate dehydrogenase.
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PMID:Increase of enzyme activities following the in vitro peroxidation of normal human red blood cells. 334 32

Our previous studies on cultured rabbit lens epithelial cells from 4-day-old rabbits showed that the glutathione redox cycle plays an important role in detoxifying H2O2, a potentially damaging oxidant present in the aqueous humor. Here we report the effect of donor age and cell density on the ability of cultured rabbit lens epithelial cells to detoxify H2O2. Lens epithelial cells (8 x 10(5] from a 4-day-old and an 8-year-old rabbit were cultured for 3 hr in minimal essential medium (MEM) or in MEM containing 0.01-0.1 mM H2O2 maintained with glucose oxidase. We determined the effect of H2O2 on the level of reduced glutathione (GSH), hexose monophosphate shunt activity, cell growth, and morphology. For growth studies, cells were exposed to the desired concentration of H2O2 for 3 hr and then cultured in MEM plus 10% rabbit serum for 7 days and counted. Young and old untreated cells contained high levels (30-40 nmol/8 x 10(5) cells) of GSH. Cells from 4-day-old rabbits tolerated 0.03 mM H2O2 with no effect on GSH and a minimal decrease in subsequent cell growth. However, in the older cells, GSH and growth were substantially diminished following treatment with 0.03 mM H2O2. Cells plated out at high density (8 x 10(5] were more tolerant of 0.03 mM H2O2 than cells plated out at low density (5 x 10(4]. Maximum shunt activity in the younger cells exposed to H2O2 was twice that of the older cells and occurred at a higher level of H2O2 (0.04 compared with 0.03 mM). Enzyme activities in untreated young and old cells were comparable for hexokinase, glucose-6-phosphate dehydrogenase, and glutathione peroxidase. However, glutathione reductase activity was 50% lower in the cells from the 8-year-old rabbit. The toxicity of H2O2 to cultured lens epithelial cells was directly related to donor age and inversely related to cell density. The damage in the older lens epithelial cells at 0.03 mM H2O2 was apparently due, in part, to a diminished response of the glutathione redox cycle to oxidative challenge.
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PMID:Influence of the activity of glutathione reductase on the response of cultured lens epithelial cells from young and old rabbits to hydrogen peroxide. 335 66

Activities of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase of calf trabecular meshwork were measured and found to be 0.23 and 0.47 mumole/min/g tissue, respectively. Glucose 6-phosphate dehydrogenase was purified 450-fold with a yield of 91% by anion exchange chromatography and 2',5'-ADP agarose affinity chromatography. It was activated by Ca2+, Mg2+, and Mn2+. It was deactivated by p-chloromecuribenzoate, p-chloromercuribenzene sulfonate, and iodoacetamide, but this deactivation could be prevented by pretreatment with cysteine or glutathione. Its rate was regulated by the NADPH/NADP+ ratio, being maximal at a ratio of 0, and negligible at a ratio of 10. At the physiological ratio of 5, its rate was approximately half maximal. On disc gel electrophoresis of both the crude and purified enzyme, seven bands of glucose 6-phosphate dehydrogenase activity could be seen. The isozyme pattern was similar to that of calf retina, but different from that of calf liver. These data suggest that trabecular meshwork is well supplied with the capacity to generate NADPH. Typical demands for NADPH may be to detoxify H2O2 and/or organic peroxides through the glutathione peroxidase/glutathione reductase system, and both generating and removing products of the "killing reaction" during phagocytosis.
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PMID:Glucose 6-phosphate dehydrogenase of calf trabecular meshwork. 371 Jul 38

Anaerobically induced NAD-linked glycerol dehydrogenase of Klebsiella pneumoniae for fermentative glycerol utilization was reported previously to be inactivated in the cell during oxidative metabolism. In vitro inactivation was observed in this study by incubating the purified enzyme in the presence of O2, Fe2+, and ascorbate or dihydroxyfumarate. It appears that O2 and the reducing agent formed H2O2 and that H2O2 reacted with Fe2+ to generate an activated species of oxygen which attacked the enzyme. The in vitro-oxidized enzyme, like the in vivo-inactivated enzyme, showed an increased Km for NAD (but not glycerol) and could no longer be activated by Mn2+ which increased the Vmax of the native enzyme but decreased its apparent affinity for NAD. Ethanol dehydrogenase and 1,3-propanediol oxidoreductase, two enzymes with anaerobic function, also lost activity when the cells were incubated aerobically with glucose. However, glucose 6-phosphate dehydrogenase (NADP-linked), isocitrate dehydrogenase, and malate dehydrogenase, expected to function both aerobically and anaerobically, were not inactivated. Thus, oxidative modification of proteins in vivo might provide a mechanism for regulating the activities of some anaerobic enzymes.
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PMID:Inactivation of glycerol dehydrogenase of Klebsiella pneumoniae and the role of divalent cations. 390 46

Favism is an acute hemolysis occurring in glucose-6-phosphate dehydrogenase (G6PD)-deficient (Mediterranean variant) individuals after intake of fava beans. Divicine (D), 2,6-diamino-4,5-dihydroxypyrimidine, is present in high amounts in the beans, and is suspected to play a role in hemolysis. Its mechanism of action was studied in a cell-free system and in G6PD (Mediterranean variant)-deficient red cells (RBC). Upon hydrolysis of the inactive beta-glucoside vicine, reduced divicine is formed. Oxygen acts as a one- or two-electron acceptor; superoxide anion and hydrogen peroxide are formed, respectively, together with the semiquinoid free-radical form of D. This free radical gives an electron spin resonance (ESR) signal, which is similar to that of the alloxan free radical. Added reduced glutathione (GSH) is rapidly oxidized with a stoichiometry of one to one, and the ESR signal is abolished. Additional GSH is oxidized by hydrogen peroxide and by a slow redox cycle which continuously regenerates oxidized D. The fast-direct and the slow-indirect oxidation result in nonstoichiometric oxidation of GSH. D added to G6PD-deficient RBC rapidly oxidizes GSH with an end point kinetics and a stoichiometry of one to one. Hydrogen peroxide and superoxide anion are scavenged in the RBC and no redox cycling is taking place. No GSH is regenerated even after long incubation periods. After the primary event, i.e., oxidation of GSH and--SH groups, a number of metabolic, rheologic, and membrane modifications, together with increased erythrophagocytosis take place in G6PD-deficient, D-treated RBC only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of action of divicine in a cell-free system and in glucose-6-phosphate dehydrogenase-deficient red cells. 609 11


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