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PubMed1993

Muscle glucose-6-phosphate dehydrogenase deficiency: restoration of enzymatic activity in hybrid myotubes.

A high level of glucose-6-phosphate dehydrogenase (G6PD) activity was observed in myoblasts and myotubes from normal human and mouse cell cultures. However, only a residual amount of activity was observed in myoblasts and myotubes obtained from G6PD-deficient patients (G6PD Mediterranean). Hybrids were formed by the fusion of normal (from human and mouse) and G6PD-deficient myoblasts (from the patients). These hybrids contained a high level of G6PD activity. Hoechst staining permitted to confirm that the enzymatic activity was not restrained to a domain near the competent nuclei. These results suggest that myoblast transplantation could be used to restore normal enzymatic activity in metabolic myopathies.

Adult↗
PubMed1995

Three new exon 10 glucose-6-phosphate dehydrogenase mutations.

Three previously undescribed mutations of the glucose-6-phosphate dehydrogenase (G6PD) gene have been documented in patients with hereditary non-spherocytic hemolytic anemia (HNSHA). In none of the cases have we been able to obtain a sufficient volume of blood to characterize the residual enzyme biochemically. "G6PD Calvo Mackenna" was due to an A-->G transition in cDNA nucleotide 1138 creating an Aat II site and resulting in a substitution of valine for isoleucine at amino acid 380. "G6PD Riley" was due to a T-->C transition at cDNA nucleotide 1139 also changing the 380 isoleucine, in this case to a threonine. "G6PD Wisconsin" was due to an C-->G transversion in cDNA nucleotide 1177, destroying a Aci I site and resulting in a substitution of glycine for arginine at amino acid 393. All of these mutations were in exon 10, where mutations that cause HNSHA appear to be clustered. We present a list of the 83 mutations of G6PD that have been documented to the end of April, 1995.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed1999

Human hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase) encoded at 1p36: coding sequence and expression.

Using the published protein sequence from a rabbit microsomal glucose-6-phosphate dehydrogenase G6PD we have isolated and sequenced a cDNA clone coding for its human equivalent, which is also known as hexose-6-phosphate dehydrogenase (H6PD) and glucose dehydrogenase. The corresponding genomic sequence is in the databases enabling its localization to chromosome 1p36. The gene spans 37 kb and consists of 5 exons, the fifth of which codes for more than half of the 89 kDa protein. The first intron is a 10 kb insertion in the 5' untranslated sequence. The predicted mRNA has an exceptionally long (6.5 kb) 3' untranslated sequence. The predicted protein shows extensive homology with X-linked G6PD, suggesting the two genes share a common ancestor but no intron positions are conserved between the two genes suggesting the gene duplication was an ancient event. The C-terminal portion of the protein is not homologous with G6PD but shows limited homology with proteins of unknown function found throughout evolution and encoded next to G6PD in various micro-organisms. Intriguingly this C-terminal portion has some homology with the N-terminal sequence of Plasmodium falciparum G6PD.

Amino Acid Sequence↗
PubMed1995

Increased induction of apoptosis in mononuclear cells of a glucose-6-phosphate dehydrogenase deficient patient.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency belongs to the most common human disorders of metabolism. In affected patients generation of free radicals causes life-threatening hemolytic crises, for example, after consumption of certain drugs and foods or after infections. Rather than erythrocytes we analyzed mononuclear white blood cells of a patient suffering from G6PD deficiency with respect to their ability to enter apoptosis after treatment with daunorubicin, ionizing radiation, or dexamethasone. The induction of apoptosis was increased in G6PD-deficient cells compared to cells from eight normal donors. In parallel, the glutathione content of mononuclear cells from the G6PD-deficient patient was significantly decreased. While in affected patients decreased life span of erythrocytes damaged by oxidative stress has long been recognized as the mechanism underlying hemolysis, peripheral leukocytes have not received similar attention. Induction of apoptosis is a relatively complex process that has been linked to cellular glutathione content. This is the first report investigating G6PD deficiency and apoptosis.

Adult↗
PubMed1986

Developmental variation in effects of the second and third chromosomes on the activities of the glucose 6-phosphate and 6-phosphogluconate dehydrogenases in Drosophila melanogaster.

Developmental profiles of the second- and third-chromosome modifiers of the activities of glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in Drosophila melanogaster were investigated. Third-chromosome modifiers showed very strong effects on both enzyme activities at larval, pupal, and adult stages, whereas second-chromosome effects were detected mainly at larval and adult stages. For both enzyme activities and both chromosomes, the correlation over line means between larval and pupal stages was significantly positive, but the correlation between larval or pupal stage and adult stage was not significant. This result suggests that the actions of modifiers on G6PD and 6PGD activities are influenced by the change of developmental stages. Correlation between G6PD and 6PGD activities was positive and highly significant throughout the developmental stages for both sets of chromosomes, although third-chromosome correlations were slightly higher than second-chromosome correlations. The magnitude of the correlation between G6PD and 6PGD activities does not seem to be influenced by the change of development. Diallel crosses for both sets of chromosomes indicate that the action of activity modifiers is mainly additive for both sets of chromosomes, but dominance effects were detected in some cases in adult males. Significant maternal effects were detected for the third chromosome for both enzyme activities until the pupal stage. The change of the activity modifier action after emergence of the imago and the significant correlation between G6PD and 6PGD activities were also detected for diallel progeny.

Animals↗
PubMed1982

Glucose-6-phosphate dehydrogenase deficiency in Papua New Guinea. The description of 13 new variants.

A total of 362 males from various regions of Papua New Guinea were screened for red cell glucose-6-phosphate dehydrogenase (G6PD) activity. Twenty-six G6PD deficient individuals were identified. Biochemical characterization of G6PD purified from these subjects has revealed 13 new variants and several copies of previously described forms of G6PD. This study illustrates the extreme heterogeneity of G6PD deficiency among the people of Papua New Guinea.

Electrophoresis, Starch Gel↗
PubMed1976

Transfer of the human X chromosome to human--Chinese hamster cell hybrids via isolated HeLa metaphase chromosomes.

Evidence is presented for the uptake of the human X chromosome by human-Chinese hamster cell hybrids which lack H P R T activity, following incubation with isolated human HeLa S3 chromosomes. Sixteen independent clonal cell lines were isolated in H A T medium, all of which contained a human X chromosome as determined by trypsin-Giemsa staining. The frequency of H A T-resistant clones was 32 x 10(-6) when 10(7) cells were incubated with 10(8) HeLa chromosomes. Potential reversion of the hybrid cells in H A T medium was less than 5 x 10(-7). The 16 isolated cell lines all contained activity of the human X-linked marker enzymes H P R T, P G K,alpha-Gal A, and G6PD, as determined by electrophoresis. The phenotype of G6PD was G6PD A, corresponding to G6PD A in HeLa cells. The human parental cells used in the fusion to form the hybrids had the G6PD B phenotype. The recipient cells gave no evidence of containing human X chromosomes. These results indicate that incorporation and expression of HeLa X chromosomes is accomplished in human-Chinese hamster hybrids which lack a human X chromosome.

Animals↗
PubMedDate not supplied

Amino acid conservation and clinical severity of human glucose-6-phosphate dehydrogenase mutations.

More than a hundred naturally occurring mutations of human glucose-6-phosphate dehydrogenase (G6PD) have been identified at the amino acid level. The abundance of distinct mutation sites and their clinical manifestations make this enzyme ideal for structure-function analysis studies. We present here a sequence and structure combined analysis by which the severity of clinical symptoms resulting from point mutations of this enzyme is correlated with quantified degrees of amino acid conservation within 23 G6PD sequences from different organisms. Our analysis verifies, on a quantitative basis, a widely held notion that clinically severer mutations of G6PD usually occur at conserved amino acids. However, marked exceptions to this general trend exist which are most notably revealed by a number of mutations associated with chronic nonspherocytic hemolytic anemia (class I variants). When mapped onto a homology-derived structural model of human G6PD, these class I mutational sites of low amino acid conservation appear to localize in two spatially distinct clusters, both of which are populated with mutations consisting mainly of clinically severer variants (i.e. class I and class II). These results of computer-assisted analyses contribute to a further understanding of the structure-function relationships of human G6PD deficiency.

Amino Acid Sequence↗
PubMed1989

Four tandem defective P elements associated with positive regulation of the Drosophila melanogaster glucose-6-phosphate dehydrogenase gene.

Three high-glucose-6-phosphate dehydrogenase (G6PD)-activity mutants (2512H, S44H, and 1FH) are characterized by two insertion sequences associated with the G6PD locus; one (Ins1; 3.5 kb long in 2512H and S44H and 2.9 kb long in 1FH) is present just 5' to exon I and consists of a KP' (the 32nd base of the KP was replaced by guanine), a core sequence and a KP, and the other is 4.2 kb long and resides within an intron. Southern blot analyses of revertants showing low G6PD activity suggested that the insertion sequence responsible for high G6PD activity may be the core sequence but not the flanking KP and KP' or the Ins2. DNA sequencing data of the clone carrying the core sequence of 2512H demonstrated that the core sequence is another type of defective P elements (core P). Interestingly, a protein(s) was found in the nuclear extract of Canton S embryos that specifically binds to the core P but not to the KP or various fragments of p pi 25.1. In addition, the mutant G6PD activity was found to be affected not only by the genotype, but also by cytoplasmic factors.

Animals↗
PubMed1977

Influence of fasting-refeeding and dietary linoleate on liver glucose-6-phosphate dehydrogenase and phospholipid fatty acid composition in rats adapted to a purified diet.

Responses to refeeding after fasting were studied in male rats fed a purified casein-sucrose diet containing 5% safflower oil. After a 48 hr fast, the rats were fed either the same diet or the same diet minus oil (fat-free diet). These experiments were designed to distinguish changes due to fasting and refeeding alone without a change of diet from those changes caused by refeeding a diet of different composition. In the first experiment, rats were refed for 3 or 7 days. In rats refed either diet, liver glucose-6-phosphate dehydrogenase (G6PD) activity was elevated above refasting levels, but after 7 days, activity in rats refed the 5% safflower oil diet was significantly lower than in those refed the fat-free diet. The amount of liver arachidonate in rats refed the safflower oil diet was the same during refeeding as before fasting. In the second experiment, rats were refed the fat-free diet for 1, 2, 3, or 7 days. Liver G6PD and fatty acid synthetase were measured, as well as fatty acids in liver total lipids and phospholipids. G6PD activity increased above prefasting levels after one day refeeding and continued to increase for 7 days. Fatty acid synthetase activity increased for the first 3 days of refeeding, with no additional increase after 7 days. In all rats refed the fat-free diet, the proportions of arachidonate and linoleate in liver phospholipids diminished with time, and eicosatrienoate appeared. These results show that (a) maintenance of liver phospholipid arachidonate did not prevent increased G6PD activity in early refeeding, but the elevated G6PD activity later declined when phospholipid arachidonate was maintained by feeding a source of linoleate; (b) the metabolic state of fasted-refed rats had not returned to prefasting conditions even after 7 days of refeeding a linoleate-rich diet to which the rats were adapted before fasting.

Animals↗
PubMed2004

Glucose-6-phosphate dehydrogenase deficiency in India.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red cell enzymopathy in humans and has an X-linked inheritance. It has been reported from India more than 30 years ago and the prevalence varies from 0-27% in different caste, ethnic and linguistic groups. The major clinical manifestations are drug induced hemolytic anemia, neonatal jaundice and chronic non-spherocytic hemolytic anemia. Individuals with G6PD deficiency have a selective advantage against falciparum malaria. Thirteen biochemically characterized variants have been reported from India. At the molecular level, G6PD Mediterranean is the most common deficient variant in the caste groups whereas, G6PD Orissa is more prevalent among the tribal of India. The third common variant seen in India is G6PD Kerala-Kalyan.

Anemia, Hemolytic↗
PubMed2001

Two novel glucose-6-phosphate dehydrogenase variants found in newborn mass-screening for galactosaemia.

UNLABELLED: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder in which haemolytic anaemia is the major symptom. The Beutler spot test employed in mass-screening for galactosaemia in newborns requires several intrinsic erythrocyte enzymes such as G6PD for its reaction and can theoretically detect G6PD deficiency apart from galactose-1-phosphate uridyltransferase deficiency. In this study, we detected two patients with G6PD deficiency using the quantitative Beutler test which was recently developed in our laboratory. Both patients lacked erythrocyte G6PD activity but exhibited no clinical symptoms. Molecular analysis in patients 1 and 2 revealed two novel missense mutations of C853T causing R285C and A1220C causing K407T, respectively. Molecular rather than enzymatic analysis was required in familial studies to detect and diagnose the carrier state. To date these patients have avoided oxidant stress and haemolytic diatheses have not been induced. CONCLUSION: Our results indicate that the quantitative Beutler test can detect glucose-6-phosphate dehydrogenase deficiency of class 1 and 2 and is therefore useful for early intervention and prevention of haemolytic diathesis in patients with this disorder.

Galactosemias↗
PubMed1992

13C and 31P NMR studies of glucose and 2-deoxyglucose metabolism in normal and enzyme-deficient human erythrocytes.

The flux of 13C-labeled glucose through the Embden-Meyerhof and pentose phosphate pathways was studied by 13C NMR in intact erythrocytes isolated from normal subjects or from patients suffering of glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49) deficiency. Similar rates of glucose catabolism and similar fluxes of the 13C-label into 2,3-bisphosphoglycerate and lactate were found, under basal conditions, in normal and in G6PD-deficient erythrocytes incubated in the presence of either [1-13C]- or D[6-13C]glucose. Exposure to oxidative stress by preincubation with tert-butylhydroperoxide induced in normal, but not in G6PD-deficient erythrocytes, a significant enhancement of glucose consumption, as well as a substantial reduction in 13C-label transfer from C1-glucose into lactate. It was also possible, by 31P NMR, to evaluate the conversion of 2-deoxyglucose to its phosphate-containing metabolites. The oxidation and subsequent decarboxylation of 2-deoxyglucose-6-phosphate was assessed in reconstituted systems and could subsequently be evidenced also in ethanolic extracts from normal (but not from G6PD-deficient) erythrocytes which had been exposed to oxidative stress. The results indicate that, in terms of glucose flux through the glycolytic pathway, there is little or no difference between normal and G6PD-deficient erythrocytes, regardless of previous exposure to oxidative stress. Faster consumption of either glucose or 2-deoxyglucose is induced, only in normal cells, by treatment with tert-butylhydroperoxide, essentially as a consequence of the activation of the pentose-phosphate pathway.

2,3-Diphosphoglycerate↗
PubMed1984

Plasmodium falciparum: thiol status and growth in normal and glucose-6-phosphate dehydrogenase deficient human erythrocytes.

Thiol status and growth in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes. Experimental Parasitology 57, 239-247. The relationship of the thiol status of the human erythrocyte to the in vitro growth of Plasmodium falciparum in normal and in glucose-6-phosphate dehydrogenase (G6PD)-deficient red cells was investigated. Pretreatment with the thiol-oxidizing agent diamide led to inhibition of growth of P. falciparum in G6PD-deficient cells, but did not affect parasite growth in normal cells. Diamide-treated normal erythrocytes quickly regenerated intracellular glutathione (GSH) and regained normal membrane thiol status, whereas G6PD-deficient cells did not. Parasite invasion and intracellular development were affected under conditions in which intracellular GSH was oxidized to glutathione disulfide and membrane intrachain and interchain disulfides were produced. An altered thiol status in the G6PD-deficient erythrocytes could underlie the selective advantage of G6PD deficiency in the presence of malaria.

Diamide↗
PubMed1989

Modulation of hepatic glucose-6-phosphate dehydrogenase activity in male and female rats by estrogen.

The effect of estradiol-17 beta on the activity of glucose-6-phosphate dehydrogenase was studied in both male and female rats to further characterize the sex differences in the activity of this enzyme. Four groups of intact and castrated rats were implanted subcutaneously with graded doses (2.4, 4.8 and 7.2 micrograms/day) of pelleted estradiol in a physiologically relevant experimental system. After fourteen days the rats were sacrificed and their livers were assayed for G6PD activities. The result indicated that: (i) the enzyme activity was 3-fold higher in normal adult female than in male rats, (ii) low doses of E2 (2.4, 4.8 and 7.2 micrograms/day) increased the activity of G6PD 6-fold in castrated males and over 2-fold in female castrates as well as intact rats (iii) E2 stimulation of G6PD activity appears to be more effective in castrated males than in female rats (IV) sex difference in the activity of G6PD disappeared after treatment with E2 in castrated rats. It is concluded that the activity of G6PD in rats is markedly enhanced by low doses of E2, which appears to be largely responsible for the sex differences in the activity of this enzyme in rats.

Animals↗
PubMed1995

Determinants of hydroperoxide detoxification in diabetic rat intestine: effect of insulin and fasting on the glutathione redox cycle.

The capacity for hydroperoxide detoxification in diabetic (DM) intestine was studied in streptozocin-induced DM rats by quantification of the intestinal glutathione (GSH) redox cycle, a key cellular pathway for peroxide elimination. A role for luminal glucose in regulation of redox cycle activity was examined in insulin-treated or 24-hour-fasted DM animals. Intestinal activities of the redox enzymes, GSH peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase (G6PD), were significantly decreased by 17 hours' insulin treatment, whereas only G6PD was decreased by fasting. Mucosal GSH levels were also markedly decreased under these conditions. These results are consistent with an overall suppression of intestinal GSH redox cycle function by short-term administration of insulin. Insulin treatment for 7 consecutive days increased hepatic G6PD activity by fourfold but was without effect on intestinal G6PD, suggesting tissue specificity in insulin regulation of G6PD. The rate of metabolism of tert-butyl hydroperoxide (tBH) in isolated enterocytes was low in the absence of substrates (0.51 +/- 0.07 nmol/10(6) cells/min) but was increased fivefold by exogenous glucose (2.70 +/- 0.11 nmol/10(6) cells/min), indicating that glucose availability is an important contributor to intestinal detoxification of toxic hydroperoxides. Collectively, the current results show that GSH redox cycle enzymes in DM intestine are under coordinate insulin control, and that this control appears to be downregulated by short-term insulin treatment.

Animals↗
PubMed1975

Ploidy level and mutation to hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT) deficiency in Chinese hamster cells.

The X-ray induction of 8-azaguanine (AG) resistent mutants in two sets of diploid and tetraploid Chinese hamster cells (DON and V79) was investigated. It was found that (i) the induced mutant frequencies in diploid and tetraploid cells appeared to be of the same order of magnitude and (ii) all mutants showed almost complete loss of hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT) activity except that in the tetraploid V79 cells 50--100% of activity was retained. The gene--dosage effect for glucose-6-phosphate dehydrogenase (G6PD) in these cells make it possible to determine the number of chromosomes bearing the HGPRT-gene in mutants by measuring the G6PD activity per cell. The results show that the spontaneous and induced mutants from the diploid V79 and DON as well as the tetraploid DON cells retained the G6PD activity of the parental cells, whereas the induced mutants from the tetraploid V79 cells had about 35% of the parental G6PD activity. With 6-thioguanine (TG) as selective agent, the induced mutant frequencies in diploid and tetraploid DON cells and in diploid V79 cells appeared to be of the same order of magnitude but no mutants could be recovered from tetraploid V79 cells in a single step. TG-resistant tetraploid V79 cells could only be obtained from the AG-resistant mutants after a second selection. The HGPRT activity was lost in these mutants and some of them showed an increase in G6PD activity. The combined data cannot be explained on the basis of a single genetic mechanism.

Alleles↗
PubMed1995

UV-light induces delayed mutations in Chinese hamster cells.

The possibility was examined that mutational events at the glucose 6-phosphate dehydrogenase locus can be delayed for significantly more than one or two cell divisions following treatment of Chinese hamster cells with UV light. To detect these later mutant events, the proportion of G6PD-mutant cells in a colony was obtained by replating cells from a single colony 5-7 days after UV irradiation and staining the resulting colonies for G6PD activity. Eight colonies out of a total of 1657 colonies from the treated population yielded G6PD-negative colonies upon replating, while no mutant clones were obtained from 947 colonies grown from untreated cells. One clone contained only mutant cells suggesting that the mutation occurred before the first cell division after irradiation. A second clone contained a 1:1 ratio of mutant to wild-type cells suggesting that the mutation occurred at the first cell division. The remaining six clones contained low numbers of mutant cells and the ratio of mutant to wild-type cells in these clones was in agreement with the theoretical ratios expected for mutations occurring at the fourth (1:13), sixth (1:63), seventh (1:127), eighth (1:255), ninth (1:511), and eleventh (1:2047) cell division after UV light exposure. G6PD-mutant cells deficient in staining activity were isolated from five clones and all have significant reductions in G6PD activity confirming the genetically stable character of these mutants. These results support the conclusion that UV light induces mutants for up to 11 cell generations after treatment of mammalian cells and suggest that mutagens can induce in mammalian DNA long-term alterations which act to increase the apparently spontaneous mutation frequency.

Animals↗