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PubMed1992

Sheep 6-phosphogluconate dehydrogenase. Revised protein sequence based upon the sequences of cDNA clones obtained with the polymerase chain reaction.

Sheep liver 6-phosphogluconate dehydrogenase (6-PGDH) is an enzyme of the pentose phosphate pathway. Evidence has appeared which suggests that the 6-PGDH protein sequence determined previously by direct analysis of the protein isolated from ovine liver is incorrect. Determining the enzyme's DNA sequence was considered to be the best way of solving the problem. In the first instance, a degenerate forward and a degenerate reverse primer were designed on the basis of the known protein sequence, and a partial-length cDNA clone was isolated from total sheep liver cDNA using the polymerase chain reaction. The clone encoded the expected part of the protein sequence. The clone was unsuccessfully used as a prime-cut probe to screen a sheep liver library and a bovine heart library. As a result, the polymerase chain reaction was utilized again to successfully generate a family of overlapping cDNA clones encoding a mature protein of 482 amino acids. The mature protein sequence encoded by the cDNA differs significantly from the sequence derived by direct analysis of the protein, but on closer examination the fundamental difference is caused by the incorrect placement of three enzyme fragments obtained by cyanogen bromide cleavage during the direct sequence analysis of the protein. Placing the fragments in the correct order results in the two sequences being virtually identical except for some minor amino acid changes between the amide and acid forms, and a small number of deletions and insertions.

Amino Acid Sequence↗
PubMed1989

6-phosphogluconate dehydrogenase typing from dried bloodstains--under Indian conditions.

As yet, there is no report available on the stability studies of 6-phosphogluconate dehydrogenase enzyme in India. 469 bloodstains prepared in the laboratory using a variety of substrates commonly encountered in case examination have been analysed by starch gel electrophoresis. The utility of this parameter under various climatic conditions prevalent in India has also been evaluated. Except in the cases of relatively fresh samples of blood, the PGD isoenzyme system seems not to be very suitable in Indian conditions.

Blood Grouping and Crossmatching↗
PubMed1983

Enzyme patterns in D. melanogaster imaginal discs: distribution of glucose-6-phosphate and 6-phosphogluconate dehydrogenase.

Distribution of glucose-6-phosphate dehydrogenase (G6PD) and 6-phospho-gluconate dehydrogenase (6PGD) in imaginal discs of Drosophila melanogaster was determined. Differential patterns of staining were found in all discs examined, i.e., eye-antennal, wing, leg, labial and genital. By using null mutants for either G6PD or 6PGD, the enzymes were shown to have the same distribution patterns. Staining with glucose-6-phosphate as a substrate resulted in the detection of both G6PD and 6PGD. Results of staining discs from homoeotic mutants indicate that the enzyme distribution patterns are under genetic control. In the presence of the homoeotic engrailed (en) mutation which transforms posterior wing compartment into anterior, the G6PD pattern of the posterior compartment of the wing disc was specifically transformed toward that of the anterior compartment. The bithorax series of homoeotic mutants was similarly investigated. The bithorax (bx3) mutation transforms the anterior part of the haltere to anterior wing blade. Similarly the G6PD pattern in the anterior haltere disc transforms to that of anterior wing disc. The complimentary transformation, postbithorax (pbx) results in a change of the posterior part of the haltere to posterior wing, which is likewise reflected in an altered staining pattern for G6PD in the posterior portion of the haltere disc. The combination of the bx3 and pbx resulted in a staining pattern of the haltere disc virtually indistinguishable from the normal wing disc.

Animals↗
PubMed1986

Quantitative analysis of X chromosome effects on the activities of the glucose 6-phosphate and 6-phosphogluconate dehydrogenases of Drosophila melanogaster.

By combining 20 X chromosomes with five autosomal backgrounds, the relative importance of these factors with respect to the activity variations of G6PD and 6PGD in Drosophila melanogaster were investigated. Analysis of variance revealed that there exist significant X chromosome, autosomal background and genetic interaction effects. The effect of the X chromosome was due mainly to the two allozymic forms of each enzyme, but some within-allozyme effects were also detected. From the estimated variance components, it was concluded that the variation attributed to the autosomal background is much larger than the variation attributed to the X chromosome, even when the effect of the allozymes is included. The segregation of the allozymes seems to account for about 10% of the total activity variation of each enzyme. The variation due to the interaction between the X chromosome and the autosomal background is much smaller than variations attributed either to the X chromosome or to the autosomal background. The interaction effect is indicated by the change of the ranking of the X chromosomes for different autosomal backgrounds. Highly significant and positive correlation between G6PD and 6PGD activities was detected. Again, the contribution of the autosomal background to the correlation was much larger than that attributed to the X chromosome.

Alleles↗
PubMed1986

The value of 6-phosphogluconate dehydrogenase (6-PGDH) activity as a marker of tumour cellularity and prognostic indicator in primary breast cancer.

The value of 6-phosphogluconate dehydrogenase (6-PGDH) activity as a cytosolic marker of tumour cellularity has been assessed, together with its use as a prognostic indicator for primary breast cancer in 87 patients over 4 years. 6-PGDH activity shows a good correlation with histologically-assessed tumour cellularity in a sample of 114 patients (correlation coefficient = 0.83). Patients whose primary breast tumour had a high 6-PGDH activity showed poor relapse-free survival times when compared to those with low 6-PGDH activities (Log Rank chi 2 = 6.87, P less than 0.01). This compared with a Log Rank chi 2 of 2.22, P less than 0.20 for oestrogen positive and negative patients. These results suggest that 6-PGDH activity is a better prognostic indicator in primary breast cancer than oestrogen receptor status.

Breast Neoplasms↗
PubMedDate not supplied

[Catalytic properties of 6-phosphogluconate dehydrogenase from rat liver in normal state and during toxic hepatitis].

Experimental toxic hepatitis is accompanied by a decrease of 6-phosphogluconate dehydrogenase (6PGD, 1.1.1.44) activity in rat liver. Enzyme preparations of 6PGD, obtained from livers of control group rats and animals with toxic exhibit the same molecular mass of 114.2 +/- 5.8 kDa. However G6PD isolated from liver of animals with toxic hepatitis exhibited altered Km and pH-optimum values. Reduced glutathione inhibited 6PGD-activity from the liver of control group rats and did not affect the enzyme from liver of animals with toxic hepatitis. Inhibition effect of oxidized glutathione is stronger in the pathological state. Malate, citrate, 2-oxoglutarate and isocitrate activated the enzyme from control animals, but did not the enzyme isolated from animals with hepatitis. Regulation of 6PGD-activity from liver of control and experimental animals by some nucleotides (NAD, ADP, AMP) and ribose-5-phosphate was also different.

Animals↗
PubMed1991

Identification of the lysine residue involved in the inactivation of lamb liver 6-phosphogluconate dehydrogenase by fluorescein 5'-isothiocyanate.

Fluorescein 5'-isothiocyanate binds almost selectively at the active site of lamb liver NADP-dependent 6-phosphogluconate dehydrogenase causing the inactivation of the enzyme. The substrate and the coenzyme protect against the loss of catalytic activity. The enzyme derivative was digested with trypsin, the labelled peptide was isolated by h.p.l.c. and its amino acid analysis allowed to establish that the inactivator binds to lysine 166 at the active site of the protein.

Animals↗
PubMed2006

Catalytic mechanism of 6-phosphogluconate dehydrogenase: a theoretical investigation.

Density functional calculations are employed to theoretically explore the mechanism of all elementary reaction steps involved in the catalytic reaction of 6-phosphogluconate dehydrogenase (6PGDH). The model systems we choose for the enzyme contain the essential parts of the cofactor (NADP+), the substrate 6-phosphogluconate (6PG), and some key residues (Lys183 and Glu190) in the active site of sheep liver 6PGDH. The effect of the apoenzyme electrostatic environment on the studied reaction is treated by the self-consistent reaction-field method. Our calculations demonstrate that the first step of the catalytic reaction is the formation of a 3-keto 6PG intermediate, which proceeds through a concerted transition state involving a hydride transfer from 6PG to NADP+, and a proton transfer from 6PG to Lys183. The second step is the elimination of a CO2 molecule from 6-PG, concomitant with a proton transfer from Lys183 to 6-PG. In the final step, a concerted double proton transfer (one from Glu190 to the substrate, another from the substrate to Lys183) results in the final product, the keto form of ribulose 5-phosphate (Ru5P). The rate-limiting step is the formation of a 3-keto 6PG intermediate, with a free energy barrier of 22.7 kcal/mol at room temperature in the protein environment, and all three steps are calculated to be thermodynamically favorable. These results are in good agreement with the general acid/general base mechanism suggested from previous experiments for the 6PGDH reaction.

Catalysis↗
PubMed1983

Growth rate-dependent regulation of 6-phosphogluconate dehydrogenase level in Escherichia coli K-12: beta-galactosidase expression in gnd-lac operon fusion strains.

The level of 6-phosphogluconate dehydrogenase is positively correlated with the cellular growth rate. To determine whether growth rate-dependent regulation of expression of gnd, which encodes this enzyme, is carried out by a transcriptional mechanism, the structural genes of the lactose operon were fused to and brought under the control of the gnd promoter through the use of phage Mu d1(Apr lac). Four independent gnd::Mu d1(Apr lac) operon fusion strains were isolated. After the Mu d1 prophage was replaced with lambda p1(209), Lac+ specialized transducing phages carrying the gnd-lac fusions were prepared. These phages were used to demonstrate that the lac genes were fused to the gnd promoter by crossing them with gnd promoter deletion mutants and with polar phage Mu cts-induced gnd mutants. A genetic map of the fusion joints was deduced. The level of beta-galactosidase in each fusion strain was the same in cells growing on acetate as in cells growing on glucose (with specific growth rate constants of 0.1 and 0.55 h-1, respectively) and was unaffected by the presence of a gnd+ gene in trans. Our results suggest that a post-transcriptional mechanism mediates growth rate-dependent regulation of gnd and that this regulation is not autogenous. Models for regulation are discussed with respect to these results and the physiology and DNA sequence of gnd.

DNA, Recombinant↗
PubMedDate not supplied

[Nature of mutations disrupting the formation of 6-phosphogluconate dehydrogenase in Drosophila melanogaster, and their suppression].

Molecular nature of lethal and semilethal mutations in the Pgd locus of D. melanogaster coding for 6-phosphogluconate dehydrogenase (6tpgd) was studied. All these mutations affect the structural gene of the Pgd locus: 3 semilethal mutations resulted in altered 6PGD molecules with the decreased catalytic activity; the remaining 8 lethals were "zero" alleles possessing mutant polypeptides inactive but capable to react with antisera against highly purified 6PGD. "Zero" or low activity alleles for glucose-6-phosphate dehydrogenase induced by ethyl methansulfonate were shown to be supressors for the lethal mutations in the Pgd locus. A monocistronic type of organization of the Pgd locus is suggested taking into account the biochemical mechanism of supression of the Pgd-lethals and their location in the structural gene coding for 6GPD.

Alleles↗
PubMed2007

Crystal structures of a bacterial 6-phosphogluconate dehydrogenase reveal aspects of specificity, mechanism and mode of inhibition by analogues of high-energy reaction intermediates.

Crystal structures of recombinant Lactococcus lactis 6-phosphogluconate dehydrogenase (LlPDH) in complex with substrate, cofactor, product and inhibitors have been determined. LlPDH shares significant sequence identity with the enzymes from sheep liver and the protozoan parasite Trypanosoma brucei for which structures have been reported. Comparisons indicate that the key residues in the active site are highly conserved, as are the interactions with the cofactor and the product ribulose 5-phosphate. However, there are differences in the conformation of the substrate 6-phosphogluconate which may reflect distinct states relevant to catalysis. Analysis of the complex formed with the potent inhibitor 4-phospho-d-erythronohydroxamic acid, suggests that this molecule does indeed mimic the high-energy intermediate state that it was designed to. The analysis also identified, as a contaminant by-product of the inhibitor synthesis, 4-phospho-d-erythronamide, which binds in similar fashion. LlPDH can now serve as a model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species.

Amino Acid Sequence↗
PubMed1990

Genetic tagging, cloning, and DNA sequence of the Synechococcus sp. strain PCC 7942 gene (gnd) encoding 6-phosphogluconate dehydrogenase.

A genetic approach was used for the cloning of the Synechococcus sp. strain PCC 7942 (Synechococcus strain R2) gnd gene which encodes 6-phosphogluconate dehydrogenase (6PGD). A restriction map of the gnd locus was prepared by Southern analysis using the Escherichia coli gene as a heterologous probe. The Synechococcus strain R2 gene was genetically tagged by restriction site-specific insertion of the nptII gene of Tn903 into a pUC19 plasmid library of Synechococcus strain R2 chromosomal DNA. Synechococcus strain R2 was transformed with this insertion mutation library, and isolates carrying the gnd::nptII gene were identified as mutants hypersensitive to incubation in the dark. The interrupted gene was cloned from one of the mutants. A plasmid carrying the gnd::nptII gene was reintroduced into Synechococcus strain R2, and kanamycin-resistant transformants were selected. Transformants arising by gene replacement were dark sensitive and missing 6PGD activity. Transformants arising by plasmid insertion were dark resistant and had 6PGD activity. The wild-type gene was then cloned from a transformant containing a plasmid insertion, making use of the restriction map derived from the interrupted gene. Synechococcus strain R2 6PGD was expressed in E. coli when the cloned gnd gene was transcribed from the lacZ promoter resident on the vector. The boundaries of the gene and the direction of transcription were determined from the phenotypes conferred by plasmids carrying deletions entering gnd from either end. The nucleotide sequence was determined. The deduced amino acid sequence of Synechococcus strain R2 6PGD has 56% homology to that of the E. coli K-12 enzyme.

Amino Acid Sequence↗
PubMed1996

Congenital 6-phosphogluconate dehydrogenase (6PGD) deficiency associated with chronic hemolytic anemia in a Spanish family.

Clinical and metabolic studies were performed in four members of a Spanish family with partial (50%) 6 phosphogluconate dehydrogenase (6PGD) deficiency. In all cases the activities of 6 phosphogluconolactone (6PGL) and glutathione reductase (GR) were normal, and the molecular characterization performed in the partially purified 6PGD from the propositus showed normal kinetic and electrophoretic patterns. Two females (the propositus and her sister) suffered from a well-compensated chronic nonspherocytic hemolytic anemia (CNSHA) and exhibited decreased RBC glutathione (GSH) stability with increased oxidative susceptibility, defined by enhanced malonyldialdehyde (MDA) generation "in vitro." The other two members of the family (the propositus's mother and brother) were clinically asymptomatic. In the propositus and her sister, RBC metabolism exhibited a markedly abnormal concentration of glycolytic intermediates, mainly characterized by striking increases in fructose 1,6 bisphosphate (50-fold), dihydroxiacetone-phosphate (20-fold) and glyceraldehyde 3-phosphate (tenfold). Although the precise mechanism of the hemolysis in the two patients is unknown, the enhanced oxidative threat observed in their RBCs may interfere in some way with the glycolytic pathway function, leading to a marked increase in certain metabolic intermediates located before the glyceraldehyde 3 phosphate dehydrogenase (GA3PD) step. Since it seems that GA3PD half-life is modulated by fluctuations of the cytosolic redox status, an "in situ" approach was simulated by using permeabilized RBCs. In these conditions, GA3PD activity was significantly lower in the propositus and her sister than in the asymptomatic members of the family and the simultaneous normal control.

Adult↗
PubMed1969

6-phosphogluconate dehydrogenase: hemizygous manifestation in a patient with leukemia.

In a study of 41 patients with chronic myelocytic leukemia, two were found to have the 6-phosphogluconate dehydrogenase heterozygous phenotype A-B, and two had the phenotype characteristic of Pd(B) homozygosity. Since one of the two with Pd(B) homozygosity was the mother of two children with the A phenotype, it was presumed that she carried a Pd(A) gene not expressed in her blood cells. his was confirmed by electrophoretic analysis of her fibroblasts, which had the A-B phenotypic pattern. Gene deletion is considered to be the most likely explanation.

Alleles↗