A multiple role for the coenzyme in the mechanism of action of 6-phosphogluconate dehydrogenase. The oxidative decarbosylation of 2-deoxy-6-phosphogluconate.
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Candida↗
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Results for “PHOSPHOGLUCONATE DEHYDROGENASE”
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[Negative cooperativity of 6-phosphogluconate dehydrogenase in rat liver].
The effect of various NADPH concentrations on the activity of rat liver 6-phosphogluconate dehydrogenase (EC 1.1.1.44) has been studied. The influence of NADPH concentrations on the enzyme cooperativity was observed. NADPH used at concentration up to 200 microM appeared to be a competitive inhibitor with respect to NADP+ without any cooperative effect towards the coenzyme (NADP+) binding. At high concentrations of NADPH (above 300 microM) the negative cooperativity displayed by the enzyme was confirmed by a significant decrease of the Hill coefficient for NADP(+)-from 1.1 +/- 0.2 down to 0.6 +/- 0.1 (p < 0.05).
Allosteric Regulation↗
6-Phosphogluconate dehydrogenase (PGD) genetics in the mouse: linkage with metabolically related enzyme loci.
An electrophoretic polymorphism of 6-phosphogluconate dehydrogenase (PGD) has been observed in the subspecies Mus musculus musculus from northern Denmark. M. m. musculus is interfertile with inbred strains of mice, and F1 hybrids with C57BL/6J show a three-banded phenotype. This pattern is consistent with a dimeric enzyme structure with codominant expression of alleles. In backcrosses and the F2 generation, PGD segregated as a singly autosomal gene, designated Pgd, closely linked to Gpd-1 on chromosome 4(1.7 +/- 1.1%). Both gene products are dimers, both require NADP, and these enzymes catalyze sequential steps in metabolism.
Alleles↗
Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis.
The synthesis and biological evaluation of three series of 6-phosphogluconate (6PG) analogues is described. (2R)-2-Methyl-4,5-dideoxy, (2R)-2-methyl-4-deoxy and 2,4-dideoxy analogues of 6PG were tested as inhibitors of 6-phosphogluconate dehydrogenase (6PGDH) from sheep liver and also Trypanosoma brucei where the enzyme is a validated drug target. Among the three series of analogues, seven compounds were found to competitively inhibit 6PGDH from T. brucei and sheep liver enzymes at micromolar concentrations. Six inhibitors belong to the (2R)-2-methyl-4-deoxy series (6, 8, 10, 12, 21, 24) and one is a (2R)-2-methyl-4,5-dideoxy analogue (29b). The 2,4-dideoxy analogues of 6PG did not inhibit both enzymes. The trypanocidal effect of the compounds was also evaluated in vitro against T. brucei rhodesiense as well as other related trypanosomatid parasites (i.e., Trypanosoma cruzi and Leishmania donovani).
Animals↗
Duplication of the structural gene for glucosephosphate isomerase and phosphogluconate dehydrogenase in Scabiosa columbaria and their phylogenetic implications in the dipsacaceae.
Zymograms of glucosephosphate isomerase (GPI) and phosphogluconate dehydrogenase (PGD) revealed three isozymes for each enzyme in the plant species Scabiosa columbaria. Intergenic heterodimers are formed between the polypeptides coded by Gpi-1 and Gpi-2 and between those coded by Pgd-1 and Pgd-2, indicating that a GPI and a PGD locus have been duplicated in the past. The ancestral genes assort independently with their duplicated gene, suggesting that the duplications have originated from a process of translocation. Linkage was found only between Gpi-1 and Pgd-2 and between Gpi-2 and Pgd-1, suggesting that the duplicated loci were located on the same translocated chromosomal segment. Both duplications are present in all other examined species of Scabiosa and in Cephalaria and Knautia, two other genera of the Dipsacaceae. The genera Succisa and Dipsacus, also belonging to the Dipsacaceae, do not show Gpi-1 activity, making Gpi-2 and Pgd-1 the most likely ancestral genes. In Succisa, the isozymes of Gpi-1 and Gpi-2 either overlap or Gpi-1 has been silenced. The combined results suggest that a chromosomal segment containing Gpi-2 and Pgd-1 has been translocated before the divergence of Scabiosa, Cephalaria, Knautia, and Succisa.
Genes, Plant↗
6-Phosphogluconate dehydrogenase from Lactococcus lactis: a role for arginine residues in binding substrate and coenzyme.
A gene encoding 6-phosphogluconate dehydrogenase (6-PGDH, EC 1.1.1. 44) was identified from the homofermentative lactic acid bacterium Lactococcus lactis, by complementation of Escherichia coli mutants. The cloned gene was then expressed to high levels in E. coli and the protein purified for kinetic analysis. The enzyme had a Km for 6-phosphogluconate of 15.4+/-1.4 microM and for NADP of 1.9+/-0.2 microM at pH 7.5. Sequence comparison of the L. lactis 6-PGDH with the corresponding enzyme derived from the pathogenic protozoan Trypanosoma brucei and sheep liver revealed the substrate-binding residues to be identical in all three species, although the three coenzyme-binding pockets differed slightly. A totally conserved arginine residue (Arg-447), believed to bind the 6-phosphate of substrate, was mutated to lysine, aspartate, alanine or tryptophan. In each case enzyme activity was lost, confirming an essential role for this residue on activity. A second arginine (Arg-34), believed to be critical in binding the 2'-phosphate of cofactor NADP+, was mutated to a tyrosine residue, as found in one atypical isoform of the enzyme in Bacillus subtilis. This alteration led to decrease in affinity for NADP+ of nearly three orders of magnitude. A second 6-PGDH gene has been identified from the genome of B. subtilis. This second isoform contains an arginine (Arg-34) in this position, suggesting that B. subtilis has two 6-PGDHs with different coenzyme specificities.
Amino Acid Sequence↗
Rapid purification of human erythrocyte 6-phosphogluconate dehydrogenase by means of affinity chromatography.
A rapid two-step procedure is reported by which homogeneous 6-Phosphogluconate dehydrogenase can be isolated from human erythrocytes. This method is based upon direct affinity chromatography of the hemolysates on adenosine 2',5'-bisphosphate-agarose (yielding a 4,500-fold purification), followed by anion exchange chromatography on a micro-column of DEAE-Sephadex. The present method represents a considerable simplification over previously available procedures for the purification of this enzyme protein from human erythrocytes.
Adenosine Diphosphate↗
Glucose-6-phosphate and 6-phosphogluconate dehydrogenases from eggs of the sea urchin, Arbacia punctulata.
1. Glucose-6-phosphate and 6-phosphogluconate dehydrogenases have been found in homogenates of Arbacia eggs; 95 per cent of the activity toward each substrate is recovered in the supernatant fraction after centrifuging at 20,000 g for 30 minutes. 2. With glucose-6-phosphate as substrate) the rate of TPN reduction by the supernatant fraction from 1 gm. wet weight unfertilized or fertilized eggs was 1.8 to 3.0 micromoles per minute; this rate is sufficient to support a rate of oxygen consumption 24 times that observed for unfertilized, and 6 times that for fertilized, eggs. Pentose was formed from glucose-6-phosphate at a rate 0.3 to 0.5 that of TPN reduction, when both rates were expressed as micromoles per minute. 3. The concentrations of glucose-6-phosphate and 6-phosphogluconate for half maximal activity were each approximately 0.00004 M for the respective enzymes in the supernatant fraction. Maximal activity toward 6-phosphogluconate was 50 to 60 per cent of that toward glucose-6-phosphate. Glucose-6-phosphate dehydrogenase activity was 50 per cent inhibited in presence of 0.00006 M 2,4,5-trichlorophenol. 4. Reduction of DPN by the supernatant fraction in presence of fructose-1,6-diphosphate and ADP was 0.1 to 0.2 micromoles per minute per gm. wet eggs, indicating that the glycolytic pathway can metabolize glucose-6-phosphate at about 5 per cent the rate at which it can be oxidized by the TPN system from unfertilized or fertilized Arbacia eggs. 5. Phosphoglucomutase, hexose isomerase, and a phosphatase for fructose-1,6-diphosphate also appear to be present in Arbacia eggs.
Animals↗
6-phosphogluconate dehydrogenase in the housefly, Musca domestica L.:evidence for inheritable 6PGD polymorphism.
Two electrophoretic variants of the 6-phosphogluconate dehydrogenase (6 PGD) enzyme have been found in the WHO/IN/Musca domestica/l housefly laboratory strain. The patterns shown by Cellogel zone electrophoresis can be fully explained by the hypothesis of two codominant autosomal alleles. On this hypothesis, a specific Pgd locus has been postulated and the symbols PgdA and PgdB have been assigned to the two alleles causing the PGD-A and PGD-B phenotypes. The bands corresponding to the homozygous phenotypes PGD-A and PGD-B have different electrophoretic mobility and staining intensity; they can be described, respectively, as "fast-weak" and "slow-thick." The heterozygous phenotype PGD-AB gives a three-banded pattern, indicative of a dimeric structure for this enzyme; this pattern is asymmetrical. Heterozygous flies have been found both among wild-type strains of recent colonization and among old established laboratory colonies. Most strains are PgdB monomorphic; up to now only three strains have been PgdA monomorphic, all of them being multimarker strains. The Pgd locus has been traced to the housefly linkage group III.
Alleles↗
Tissue specific, sex and age--related differences in the 6-phosphogluconate dehydrogenase gene expression.
Data presented in thid paper indicate that: (1) the age-related changes in 6-phosphogluconate dehydrogenase (6PGDH) activity depend on sex and tissue. No differences in the liver 6PGDH activity between young (1-month-old) males and females were found. In adult males, the activity was the same as in young animals but, in adult females, it reached the value twice as high as in the young. In adipose tissue (both white and brown) and kidney cortex, the enzyme activity decreased with age both in males and females. There were no differences between males and females 6PGDH activity in brain, heart and skeletal muscle. (2) The sex and age-related changes in the liver 6PGDH activity occur predominantly at the level of mRNA cellular concentration. (3) In the liver of ovariectomized rats decrease of 6PGDH activity and mRNA level was observed. Oestradiol administration to ovariectomized rats restored liver 6PGDH activity and liver 6PGDH mRNA levels to that observed in controls. No changes in 6PGDH activity and mRNA levels were found in white adipose tissue (WAT) of ovariectomized adult rats and in ovariectomized rats treated with oestradiol. (4) Oestradiol administration to males caused an increase of liver 6PGDH activity and mRNA levels to values observed in females, but was without an effect on WAT 6PGDH activity and mRNA level. (5) These results suggest that 6PGDH activity in different tissues is not regulated in coordinate fashion and that oestradiol plays an important role in the liver enzyme activity regulation.
Adipose Tissue↗
Influence of dietary fat on growth and liver lipid content, glucose-6-phosphate and 6-phosphogluconate dehydrogenases, and aldolase activities in the chick.
The influence of fat in chick diets containing 18, 21, and 24% protein on growth and liver lipid content, glucose 6-phosphate, and 6-phosphogluconate dehydrogenases, and aldolase activities was evaluated. Twelve percent fat in diets containing 21 and 24% protein increased the rate of growth. The fat level also decreased liver lipid content at 24% dietary protein. Improved growth was attributed to higher feed intake. However, dietary fat did not affect the activities of the above enzymes indicating their inadaptive nature to dietary fat.
Animals↗
[Purification and various biochemical and immunological properties of wild and mutant forms of Drosophila melanogaster 6-phosphogluconate dehydrogenase].
A 1500--2000-fold purification procedure using substrate elution from phosphocellulose is described for two isozymes of 6-phosphogluconate dehydrogenase (6PGD) coded for by the corresponding allelic genes. Taking into account the data of gel filtration and of SDS polyacrylamide gel electrophoresis both isozymes are shown to be dimers containing identical polypeptides of mol. weight 50 000. Antisera against the highly purified sample of 6PGD, inactivated by lyophilization completely inhibited the enzyme activity. Antigens reacting to antisera were revealed by Ouchterlony immunodiffusion tests in extracts of flies carrying the wild type or mutant Pgd allele, coding for 6PGD. In addition to 6PGD antigen (antigen 1) another protein (antigen 2) which shared no common antigenic precipitative determinants with the antigen 1 was revealed in extracts of the normal flies. Antigen 2 was demonstrated also in the six different mutants which expressed zero level of 6PGD activity and had no antigen 1. Mol weight of a 6PGD subunit and of antigen 2 purified by immobilized antibodies were shown to be identical by SDS-polyacrilamide gel electrophoresis. A transformation of "antigen 2" to "antigen 1" was performed by treatment of the former in 2% SDS-mercaptoethanol solution. As a result of SDS treatment no changes of antigenic properties of the inactivated and dissociated 6PGD dimers were observed in immunodiffusion tests.
Animals↗
Polyethylene sulfonate: a tight-binding inhibitor of 6-phosphogluconate dehydrogenase of Cryptococcus neoformans.
Polyethylene sulfonate (PES) or polyvinyl sulfonate was found to be a potent inhibitor of a number of fungal enzymes, including 6-phosphogluconate dehydrogenase from Cryptococcus neoformans. The inhibition was apparently competitive versus either NADP or 6-phosphogluconate, with 50% inhibition at PES concentrations below 10 nM. Replots of slopes of double-reciprocal plots versus inhibitor concentration were sharply concave upward, whereas replots of slope versus [PES]3 were linear. The inhibition was freely reversible upon dilution of the enzyme-PES complex. A model is presented that involves initial binding of the long (M(r) 50,000) polyanionic PES at a remote site on the enzyme, followed by interaction of the end of the tethered polymer with the binding site for NADP or for 6-phosphogluconate.
Alkanesulfonic Acids↗
Purification and cloning of chloroplast 6-phosphogluconate dehydrogenase from spinach. Cyanobacterial genes for chloroplast and cytosolic isoenzymes encoded in eukaryotic chromosomes.
Previous attempts to purify chloroplast 6-phosphogluconate dehydrogenase (cp6PGDH), a key enzyme of the oxidative pentose phosphate pathway, have been unsuccessful due to rapid activity loss. An efficient purification protocol was developed and the enzyme from spinach leaves was purified 1000-fold to apparent homogeneity with a specific activity of 60 U.mg-1. The enzyme is a homodimer with subunits of 50 kDa. Antibodies raised against the purified cp6PGDH detected a 53-kDa protein from a crude extract, indicating alterations during purification. Purified cp6PGDH was microsequenced and the corresponding spinach cDNA was cloned using PCR techniques and degenerate primers. The cDNA for cytosolic 6PGDH from spinach was cloned for comparison. Phylogenetic analysis in the context of available homologues from eukaryotes and eubacteria revealed that animal and fungal cytosolic 6PGDH sequences are more similar to their homologues from gamma-proteobacteria, whereas plant 6PGDH is more similar to its cyanobacterial homologues. The ancestral gene for higher plant 6PGDH was acquired from the antecedent of plastids through endosymbiosis and gene transfer to the nucleus. A subsequent gene duplication gave rise to higher plant cytosolic 6PGDH, which assumed the function of its pre-existing cytosolic homologue through endosymbiotic gene replacement. The protein phylogeny of both 6PGDH and of the first enzyme of the oxidative pentose phosphate pathway, glucose-6-phosphate dehydrogenase, indicate a surprisingly close relationship between the plant and Trypanosoma brucei lineages, suggesting that T. brucei (a relative of Euglena gracilis) may be secondarily nonphotosynthetic.
Amino Acid Sequence↗
Phosphoglucomutase1 and 6-phosphogluconate dehydrogenase types in human skin and adipose tissue.
Attempts were made to detect phenotypes of the enzymes phosphoglucomutase (PGM) and phosphogluconate dehydrogenase (PGD) in human skin and adipose tissues. Both enzymes could be typed using approximately 3 mg wet weight of tissue. Phenotypes could be distinguished after up to 15 days of aging for PGM and ten days of aging for PGD. Analysis of isoenzymes is potentially useful for mediolegal identification of human skin and adipose tissue.
Accidents, Traffic↗
[ON THE PROBLEM OF EARLY RECOGNITION OF GYNECOLOGIC CANCER BY ENZYME TESTS (GLUCOSE-6-PHOSPHATE AND 6-PHOSPHOGLUCONATE DEHYDROGENASE)].
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Clinical Enzyme Tests↗
A rare fast variant of red cell 6-phosphogluconate dehydrogenase found in Japanese.
In a Japanese family, we discovered by starch-gel electrophoresis a fast variant of 6-phosphogluconate dehydrogenase (PGD) in red blood cells. This variant is described here for the first time and temporarily named AX. It showed three PGD bands, the usual PGD A band and two faster-moving bands than PGD A. The ratio of the staining intensity of these bands was 2:2:1 in the order of increasing mobility, and negative sensitivity was noted toward 2-mercaptoethanol. Its genotype appeared to be heterozygous PGDA/PGDX, based on examinations of the PGD band composition and the pedigree of the family. It may possibly correspond to the PGD "Kadar" variant (PGDA/PGDKadar), with which it was quite similar, in electrophoretic mobility, staining intensity and sensitivity to 2-mercaptoethanol.
Asian People↗
Structure and expression of the Drosophila melanogaster gene encoding 6-phosphogluconate dehydrogenase.
We have determined the nucleotide sequence and structure of Pgd+, the Drosophila melanogaster gene that encodes the enzyme, 6-phosphogluconate dehydrogenase (6PGD). The derived 481-amino acid sequence for D. melanogaster 6PGD is presented and compared with 6PGD sequences from other species. To characterize the cis-acting sequences necessary for expression of Pgd+, fragments containing this gene as well as Pgd+ promoter-lacZ fusions were introduced into the D. melanogaster germ line by P-element-mediated transformation. Our results indicate that the large second intron is critical for Pgd+ expression in adults. Only 421 bp of Pgd+ 5'-flanking DNA are necessary to direct expression in imaginal discs, gonads and gut of third-instar larvae. Sequences downstream from the transcription start point are necessary for expression in the larval fat body.
Amino Acid Sequence↗