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PubMed1993

Regulation of liver glucose-6-P dehydrogenase levels in female rats.

1. Gender differences in the dietary regulation of rat liver glucose-6-P dehydrogenase activity, synthesis and mRNA levels were examined. 2. As expected, in normal rats fed a standard chow diet, females have higher G6PD activity than males because they have more G6PD mRNA and therefore a higher rate of G6PD synthesis. 3. In contrast, the decreased dietary induction in female rats is due to a more rapid rate of G6PD degradation rather than a decrease in G6PD mRNA or synthesis.

Animals↗
PubMed1990

Isolation and characterization of the ZWF1 gene of Saccharomyces cerevisiae, encoding glucose-6-phosphate dehydrogenase.

Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first step of the pentose phosphate pathway, a reaction that generates NADPH. We have isolated ZWF1, the Saccharomyces cerevisiae gene that encodes G6PD, and identified its transcript and transcription start point. Expression of ZWF1 appears not to be regulated, consistent with its 'housekeeping' role. Null mutants lacking G6PD appear to grow normally, but are more sensitive than wild type to oxidizing agents that presumably reduce the level of NADPH. This suggests that G6PD has a major role in NADPH production in yeast. Regulation of GAL1 expression appears normal in zwf1 mutants, suggesting that the pentose phosphate pathway is not involved in glucose repression. The predicted amino acid sequence of yeast G6PD is highly similar to the sequence of the Drosophila, human, and rat enzymes, except near its N terminus, where the yeast and Drosophila sequences diverge from that of human and rat.

Amino Acid Sequence↗
PubMed1993

Decreased catalase activity is the underlying mechanism of oxidant susceptibility in glucose-6-phosphate dehydrogenase-deficient erythrocytes.

Historically, it has been theorized that the enhanced oxidant sensitivity of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes arises as a direct consequence of an inability to maintain cellular glutathione (GSH) levels. This study alternatively hypothesizes that decreased NADPH concentration leads to impaired catalase activity which, in turn, underlies the observed oxidant susceptibility. To investigate this hypothesis, normal and G6PD-deficient erythrocytes and hemolysates were challenged with a H2O2-generating agent. The results of this study demonstrated that catalase activity was severely impaired upon H2O2 challenge in the G6PD-deficient cell while only a transient decrease was observed in normal cells. Supplementation of either normal or G6PD-deficient hemolysates with purified NADPH was found to significantly (P < 0.001) inhibit catalase inactivation upon oxidant challenge while addition of NADP+ had no effect. Analysis of these results demonstrated direct correlation between NADPH concentration and catalase activity (r = 0.881) and an inverse correlation between catalase activity and erythrocyte oxidant sensitivity (r = 0.906). In contrast, no correlation was found to exist between glutathione concentration (r = 0.170) and oxidant sensitivity. Analysis of NADPH/NADPt ratio in acatalasemic mouse erythrocytes demonstrated that NADPH maintenance alone was not sufficient to explain oxidant resistance, and that catalase activity was required. This study supports the hypothesis that impaired catalase activity underlies the enhanced oxidant sensitivity of G6PD-deficient erythrocytes and elucidates the importance of NADPH in the maintenance of normal catalase activity.

Animals↗
PubMed2005

The effect of Zn2+ on glucose 6-phosphate dehydrogenase activity from Bufo arenarum toad ovary and alfalfa plants.

The effect of Zn2+ on glucose 6-phosphate dehydrogenase (G6PD) activity was monitored in samples from Bufo arenarum toad ovary and alfalfa plants, in the search for a possible new bioindicator able to detect levels of exposure through contaminated soils, and also to elucidate possible similarities between the enzyme from animal and plant tissues. The in vivo effect was evaluated after exposure of the toads to the metal in Ringer solution during 30 days and after 10 days of treatment in 6 weeks old plants, cultured under laboratory conditions. In vitro effects were measured in different extracts from control samples and partially purified enzyme from ovarian tissue as well as in different extracts from control alfalfa plants, by addition of the metal to the reaction mixture containing the enzyme. G6PD from toad ovary was noncompetitively inhibited by zinc both in vivo and in vitro, under all the experimental conditions studied. A kinetic analysis of the enzyme activity showed that the Michaelis-Menten constant (Km) was not modified, while maximal velocity (Vmax) decreased as the consequence of treatment. It was not possible to obtain a dose-response curve for the effects of Zn2+ on G6PD from alfalfa whole plants, measured in vivo or in vitro. Only leaf extracts evidenced a possible relationship between treatment with the metal and G6PD activity alteration. The results agree with a possible role for G6PD as a biomarker of effect and exposure to Zn2+ in B. arenarum ovarian tissue but not in alfalfa plants.

Animals↗
PubMed2006

Cloning and characterization of an alternative transcript of ovine glucose 6-phosphate dehydrogenase gene: comparative approach between ruminant and non-ruminant species.

Glucose 6-phosphate dehydrogenase (G6PD) plays an important role in ruminant's lipogenesis, as it provides necessary compounds of NADPH for the synthesis of fatty acids catalyzing the first committed reaction in the pentose phosphate pathway. In this work the full length ovine glucose 6-phosphate dehydrogenase cDNA was isolated using a polymerase chain reaction based strategy. Two isoforms (OG6PDA and OG6PDB) were detected encoding a protein of 515 and 524 amino acids, respectively. Both deduced amino acid sequences reveal a well conserved protein containing all the important residues for its catalytic role. The extra nine amino acids encoded by OG6PDB cause a frameshift in the polypeptide chain resulting in changes around the area of the potential substrate binding site. A three-dimensional model of ovine G6PD protein shows that this frameshift cause structural changes in the catalytic binding "pocket" of the molecule. Southern blot and RT analysis revealed that ovine G6PD appears as a single copy gene while it is expressed, with slight variability, in all tissues analyzed. Moreover, expression analysis of the ovine G6PD isoforms showed that OG6PDB is expressed only in tissues where lipogenesis is high in ruminants. Thus, we hypothesize that in ruminants G6PD may be regulated by the ratio of the two transcripts, according to the existence stimulus.

Alternative Splicing↗
PubMed2026

Glucose-6-phosphate dehydrogenase variants modify 3D genomic organization to suppress maladaptive gene expression and vascular disease.

The 3D genome architecture is a higher-order organization of chromosomes within the nucleus that is critical to the control of epigenomic modifications. However, our knowledge regarding the role of 3D genomic organization in the regulation of vascular gene expression and function is lacking. In the present study, CRISPR-engineered rats modelled after two common polymorphisms (S188F and N126D) in human glucose-6-phosphate dehydrogenase (G6PD) revealed modifications to the 3D genome in aortas from rats expressing a deficient G6PD variant (S188F), but not a non-deficient one (N126D), is associated with: 1] up-regulated expression of TET enzymes that augmented expression of genes encoding antiproliferative proteins, 2] suppressed expression of genes encoding inflammatory/thrombotic/fibrotic proteins, and 3] reduced angiotensin II-induced aortic stiffness and hypertension. G6PD interacted with MATRIN-3, a nuclear matrix/scaffold protein, and a deficient G6PD variant increased the relative abundance of MATR3 and CCCTC-binding factors, potentially modifying 3D-genome structure. Additionally, G6PD deficiency-induced enrichment of H3K27ac likely influences the establishment and maintenance of the 3D genome. Therefore, we propose that the nexus between metabolism and the 3D genome regulates arterial gene expression and vascular disease.

Animals↗
PubMed2004

Effects of antiemetic drugs on glucose 6-phosphate dehydrogenase and some antioxidant enzymes.

The aim of this study was to investigate effect of antiemetics on G6PD and antioxidant enzymes. Antiemetics are currently being used to reduce or prevent nausea and vomiting in patients. This is the first study to show effect of antiemetics on glucose-6-phosphate dehydrogenase (G6PD) and antioxidant enzyme activities. For in vitro studies, G6PD was purified from human erythrocyte, 10, 26-fold in a yield of 51.3% by using ammonium sulphate precipitation and 2',5'-ADP-Sepharose 4B affinity gel. The purified enzyme showed a single band on sodium dodecyl sulfate-polyacrilamide gel electrophoresis (SDS-PAGE). The effects of four different antiemetics (granisetron hydrochloride, ondansetron hydrochloride, metoclopramide hydrochloride, trimethobenzamide hydrochloride) were investigated on the purified enzyme. Granisetron hydrochloride and ondansetron hydrochloride inhibited the enzyme activity (Ki values; 5.05 mM and 0.034 mM, I50 values; 3.9 mM and 0.036 mM, respectively). Metoclopramide hydrochloride, trimethobenzamide hydrochloride showed no inhibition effects. In addition, in vivo studies, effects of ondansetron hydrochloride on the G6PD, glutathione reductase (GR), glutathione peroxidase (GPx) and catalase (CAT) were examined in the rat erythrocytes. G6PD (49% of control), GR (55% of control), CAT (60% of control) activities in erythrocytes were significantly decreased whereas GPx (183% of control) was significantly increased. A marked alteration in these enzymes may be result of oxidative stress in the rats receiving ondansetron hydrochloride.

Animals↗
PubMed2006

Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart.

In the failing heart, NADPH oxidase and uncoupled NO synthase utilize cytosolic NADPH to form superoxide. NADPH is supplied principally by the pentose phosphate pathway, whose rate-limiting enzyme is glucose 6-phosphate dehydrogenase (G6PD). Therefore, we hypothesized that cardiac G6PD activation drives part of the excessive superoxide production implicated in the pathogenesis of heart failure. Pacing-induced heart failure was performed in eight chronically instrumented dogs. Seven normal dogs served as control. End-stage failure occurred after 28 +/- 1 days of pacing, when left ventricular end-diastolic pressure reached 25 mm Hg. In left ventricular tissue homogenates, spontaneous superoxide generation measured by lucigenin (5 microM) chemiluminescence was markedly increased in heart failure (1338 +/- 419 vs. 419 +/- 102 AU/mg protein, P < 0.05), as were NADPH levels (15.4 +/- 1.5 vs. 7.5 +/- 1.5 micromol/gww, P < 0.05). Superoxide production was further stimulated by the addition of NADPH. The NADPH oxidase inhibitor gp91(ds-tat) (50 microM) and the NO synthase inhibitor L-NAME (1 mM) both significantly lowered superoxide generation in failing heart homogenates by 80% and 76%, respectively. G6PD was upregulated and its activity higher in heart failure compared to control (0.61 +/- 0.10 vs. 0.24 +/- 0.03 nmol/min/mg protein, P < 0.05), while superoxide production decreased to normal levels in the presence of the G6PD inhibitor 6-aminonicotinamide. We conclude that the activation of myocardial G6PD is a novel mechanism that enhances NADPH availability and fuels superoxide-generating enzymes in heart failure.

6-Aminonicotinamide↗
PubMed2001

Glucose-6-phosphate dehydrogenase supports the functioning of the synapses in rat cerebellar cortex.

This study investigates heterogeneous glucose-6-phosphate dehydrogenase (G6PD) expression in the rat cerebellar cortex. G6PD activity and its electrophoretic pattern, evaluated on the cerebellar homogenate, were found to be similar to those of other brain areas. However, histochemical and immunohistochemical analyses revealed that the highest expression of G6PD activity and protein was in Purkinje's cells, followed by the molecular and granular layers. Electron microscopy analysis showed that, in Purkinje's cells, the G6PD reaction products were concentrated in the neurites while in the basket cells in the cell body. The granules showed a weaker activity everywhere. The quantitative distribution of G6PD is discussed in the light of the neurochemical function of these cells.

Animals↗
PubMed1998

Impaired production of nitric oxide, superoxide, and hydrogen peroxide in glucose 6-phosphate-dehydrogenase-deficient granulocytes.

Since the generation of superoxide and hydrogen peroxide by NADPH oxidase and nitric oxide (NO) by NO synthase (NOS) in granulocytes is NADPH-dependent, we investigated the production of NO, superoxide and H2O2 in glucose 6-phosphate dehydrogenase (G6PD)-deficient human granulocytes. Our results showed that upon stimulation with either 5 microg/ml of lipopolysaccharide (LPS) or 10 microM of phorbol 12-myristate 13-acetate (PMA), the production of nitrite in normal granulocytes was elevated, 252 +/- 135% and 239 +/- 72%, respectively, compared to the resting stage. In contrast, G6PD-deficient granulocytes did not produce more nitrite upon stimulation with either LPS or PMA compared to the resting stage. Western blot analysis indicated a normal expression pattern of inducible NOS in G6PD-deficient granulocytes. In addition, the production of H2O2 and superoxide was also significantly impaired in G6PD-deficient granulocytes compared to control cells. These data demonstrate that G6PD deficiency causes an impairment in the production of NO, superoxide and H2O2.

Erythrocytes↗
PubMed1998

Molecular anatomy of the human glucose 6-phosphate dehydrogenase core promoter.

The gene encoding glucose 6-phosphate dehydrogenase (G6PD), which plays a pivotal role in cell defense against oxidative stress, is ubiquitously expressed at widely different levels in various tissues; moreover, G6PD expression is regulated by a number of stimuli. In this study we have analyzed the molecular anatomy of the G6PD core promoter. Our results indicate that the G6PD promoter is more complex than previously assumed; G6PD expression is under the control of several elements that are all required for correct promoter functioning and, furthermore, a still unidentified mammalian specific factor is needed.

Animals↗
PubMed1991

Screening for glucose-6-phosphate dehydrogenase deficiency as a preventive measure: prevalence among 1,286,000 Greek newborn infants.

We evaluated the Greek screening program for glucose-6-phosphate dehydrogenase (G6PD) deficiency, which was incorporated into the existing national phenyketonuria (PKU) screening program to identify infants with G6PD deficiency and eliminate the induction of acute hemolytic crisis by informing the families about the extrinsic factors that G6PD-deficient patients should avoid. Between 1977 and 1989, 1,286,000 infants were screened. The fluorescent spot test was used on samples extracted from dried blood spots. Abnormal fluorescence due to G6PD deficiency (severe or partial) was found in 3.14% of the samples (1 in 22 males and 1 in 54 females). The sensitivity of the test for homozygosity and hemizygosity was 100%. In heterozygosity the test identifies only subjects who have considerably diminished enzyme activity. The test is inexpensive when added to the PKU screening program ($0.90 US per test). We believe that screening a population for G6PD deficiency is justified if the incidence of the deficiency in the population is high and the clinical manifestations serious. The fluorescent spot test is recommended because it is reliable, easy to perform, and inexpensive. The test must be performed within a fortnight from sampling, and the cards must not be exposed to high temperature or humidity.

False Negative Reactions↗
PubMed1995

Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentrations associated with bilirubin-related morbidity and death in Nigerian infants.

Our objective was to determine whether glucose-6-phosphate dehydrogenase (G6PD) deficiency and elevated carboxyhemoglobin (COHb) levels correlated with bilirubin-related morbidity and mortality rates. For this purpose, we studied 55 clinically jaundiced infants admitted to a rural mission hospital in southern Nigeria. Total serum bilirubin levels (range, 80 to 1016 mumol/L (4.7 to 59.4 mg/dl)) correlated with the percentage COHb concentrations (COHb = 0.45 + 0.08 Total serum bilirubin; r = 0.72). Infants were divided into two groups of equal size around the median COHb concentration (COHb range, 0.43% to 5.93% (median = 1.40%), with ambient carbon monoxide of 0.65 +/- 0.03 microL/L). The COHb levels > or = 1.40% were associated with the need for exchange transfusion (15/28, or 54%, vs 5/27, or 19%; p < 0.01) and with an increased incidence of clinical findings compatible with kernicterus (9/28, or 32%, vs 0/27, or 0%; p < 0.01). Mortality rate was 29% (8/29) among infants with higher COHb levels, and 7% (2/28) in those with lower levels (p = 0.08). Thirty-one percent (14/45) of the clinically jaundiced infants tested had G6PD deficiency. Thirty-six percent of the infants with G6PD deficiency died with presumed kernicterus, compared with only 3% (1/31) of the infants with a normal G6PD screening test result (p < 0.01). These data suggest that G6PD deficiency and increased bilirubin production, as indexed by COHb, are associated with jaundice-related morbidity and death in Nigerian infants.

Bilirubin↗
PubMed1993

Mitogenic action of insulin-like growth factor-I on human osteosarcoma MG-63 cells and rat osteoblasts maintained in situ: the role of glucose-6-phosphate dehydrogenase.

The mechanisms involved in the mitogenic actions of insulin-like growth factor-I (IGF-I) on skeletal cells are at present unclear. We have investigated the role of glucose-6-phosphate dehydrogenase (G6PD) in this mechanism and provide strong evidence that stimulation of G6PD activity is required for the growth promoting activities of IGF-I. IGF-I (10 ng/ml) significantly elevated G6PD activity in MG-63 human osteosarcoma cells within 30 min which preceded the IGF-I induced DNA synthesis in these cells. Inhibition of G6PD activity by epiandrosterone decreased DNA synthesis in IGF-I stimulated MG-63 cells but this was partly overcome by the addition of a combination of the four deoxyribonucleosides. IGF-I did not cause a general increase in cell metabolism as succinate dehydrogenase and iso-citrate dehydrogenase activity were not altered. Although IGF-I caused a significant increase in lactate dehydrogenase activity this was not inhibited by epiandrosterone. The culture of metatarsals of 4-week-old rats with IGF-I (10 ng/ml) also stimulated G6PD activity in osteoblasts lining the metaphyseal trabeculae.

Androsterone↗
PubMed2002

Crocidolite asbestos inhibits pentose phosphate oxidative pathway and glucose 6-phosphate dehydrogenase activity in human lung epithelial cells.

The cytotoxicity of asbestos has been related to its ability to increase the production of reactive oxygen species (ROS), via the iron-catalyzed reduction of oxygen and/or the activation of NADPH oxidase. The pentose phosphate pathway (PPP) is generally activated by the cell exposure to oxidant molecules. Contrary to our expectations, asbestos (crocidolite) fibers caused a dose- and time-dependent inhibition of PPP and decreased its activation by an oxidative stress in human lung epithelial cells A549. In parallel, the intracellular activity of the PPP rate-limiting enzyme, glucose 6-phosphate dehydrogenase (G6PD), was significantly diminished by crocidolite exposure. This inhibition was selective, as the activity of other PPP and glycolysis enzymes was not modified, and was not attributable to a decreased expression of G6PD. On the opposite, the incubation with glass fibers MMVF10 did not modify PPP and G6PD activity. PPP and G6PD inhibition did not correlate with the increased nitric oxide (NO) production elicited by crocidolite in A549 cells. Experiments with the purified enzyme suggest that crocidolite inhibits G6PD by directly interacting with the protein. We propose here a new mechanism of asbestos-evoked oxidative stress, wherein fibers increase the intracellular ROS levels also by inhibiting the main antioxidant pathway of the cell.

Asbestos, Crocidolite↗
PubMed2003

Redox imbalance and mutagenesis in spleens of mice harboring a hypomorphic allele of Gpdx(a) encoding glucose 6-phosphate dehydrogenase.

Mice harboring the activity-attenuated Gpdx(a-m2Neu) allele and also harboring a chromosomally integrated lacZ reporter gene to study mutagenesis (pUR288) were used to demonstrate that moderate glucose 6-phosphate dehydrogenase (G6PD) deficiency causes elevated mutagenesis and endogenous oxidative stress in the spleen. G6PD-deficient spleens with a residual enzyme activity of 22% exhibited a dramatic shift in the mutational pattern of lacZ (4.6-fold increase in the prevalence of recombination mutations of lacZ) together with a 1.8-fold increase in mutant frequencies in lacZ. A concomitant 3-fold reduction in catalase activity (dependent upon NADPH) indicated that the in vivo supply of G6PD-generated NADPH was insufficient. An additional 3-fold increase in oxidized glutathione suggested that redox control was disturbed in G6PD-deficient spleens. These findings indicate that G6PD is required for limiting oxidative mutagenesis in the mouse spleen. Gpdx(a-m2Neu) is the first hypomorphic allele of a mouse housekeeping gene associated with elevated somatic mutagenesis in vivo.

Alleles↗
PubMed2000

alpha-crystallin protects glucose 6-phosphate dehydrogenase against inactivation by malondialdehyde.

The present work investigates the effect of malondialdehyde (MDA) binding on the enzymic activity and on some structural properties of glucose 6-phosphate dehydrogenase (G6PD). We studied whether alpha-crystallin could protect the enzyme against MDA damage, and if so, by what mechanism. We also studied whether alpha-crystallin could renature G6PD denatured by MDA. alpha-Crystallin was prepared from bovine lenses by gel chromatography. MDA was freshly prepared and incubated with G6PD with or without alpha-crystallin. The results show that MDA reacted with G6PD non-enzymically causing inactivation at concentrations lower than those used previously on structural proteins. The modified enzyme became fluorescent. alpha-Crystallin, acting as a molecular chaperone, specifically protected the enzyme against inactivation by MDA. The enzyme was not reactivated by alpha-crystallin, but it was stabilised and protected against further denaturation. Complex formation between alpha-crystallin and the modified enzyme was demonstrated by immunoprecipitation. G6PD was very susceptible to MDA and we have shown for the first time that alpha-crystallin is able to protect the enzyme against this damage.

Animals↗
PubMedDate not supplied

Combined glucose-6-phosphate dehydrogenase and glucosephosphate isomerase deficiency can alter clinical outcome.

Glucosephosphate isomerase (GPI) deficiency in humans is an autosomal recessive disorder, which results in nonspherocytic hemolytic anemia of variable clinical expression. A 4-year-old female with severe congenital hemolytic anemia had low red cell GPI activity of 15.5 IU/g Hb (50% of normal mean) indicating GPI deficiency. Subsequent DNA sequence analysis revealed a novel homozygous 921C to G mutation in the GPI gene sequence, predicting a Phe307 to Leu replacement. Strikingly, the red cell GPI activity in this patient was higher than that found in a second patient expressing the same GPI variant, with a more severe clinical phenotype. We propose that the hemolysis in the first patient may be modified by an accompanying deficiency of glucose-6-phosphate dehydrogenase (G6PD). The proband's red cell G6PD activity was reduced at 4.5 IU/g Hb (50% of normal mean) and molecular studies revealed heterozygosity for the G6PD Viangchan mutation and a skewed pattern of X-chromosome inactivation, producing almost exclusive expression of the mutated allele. The G6PD Viangchan variant is characterised by severe enzyme deficiency, but not chronic hemolysis. This study suggests that the metabolic consequences of a combined deficiency of GPI and G6PD might be responsible for a different clinical outcome than predicted for either defect in isolation.

Anemia, Hemolytic↗