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PubMed1995

Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress.

Glucose 6-phosphate dehydrogenase (G6PD) is a housekeeping enzyme encoded in mammals by an X-linked gene. It has important functions in intermediary metabolism because it catalyzes the first step in the pentose phosphate pathway and provides reductive potential in the form of NADPH. In human populations, many mutant G6PD alleles (some present at polymorphic frequencies) cause a partial loss of G6PD activity and a variety of hemolytic anemias, which vary from mild to severe. All these mutants have some residual enzyme activity, and no large deletions in the G6PD gene have ever been found. To test which, if any, function of G6PD is essential, we have disrupted the G6PD gene in male mouse embryonic stem cells by targeted homologous recombination. We have isolated numerous clones, shown to be recombinant by Southern blot analysis, in which G6PD activity is undetectable. We have extensively characterized individual clones and found that they are extremely sensitive to H2O2 and to the sulfydryl group oxidizing agent, diamide. Their markedly impaired cloning efficiency is restored by reducing the oxygen tension. We conclude that G6PD activity is dispensable for pentose synthesis, but is essential to protect cells against even mild oxidative stress.

Animals↗
PubMed1977

Pentose utilizing variants of Novikoff hepatoma cells: modification of growth and morphological properties.

A series of variant lines that utilize multiple pentoses for growth in place of glucose have been isolated from an 8-azaguanine resistant line of Novikoff hepatoma cells (N1S167). These variants utilize for growth ribose, xylose, arabinose, and/or deoxyribose. The variants growing on pentose containing medium (a) exhibit a density dependent cessation of growth, (b) have a morphology change to a more flattened cell type, (c) become binucleated in the presence of cyto chalasin B, and (d) show an altered sensitivity to trypsin treatment.

Arabinose↗
PubMed1993

Estimates of glycolysis, pyruvate (de)carboxylation, pentose phosphate pathway, and methyl succinate metabolism in incapacitated pancreatic islets.

Pancreatic islets were cultured for 24 h in the presence of 1 mM glucose, which renders islets incapable of responding to glucose with insulin release. These islets were compared to islets maintained at 20 mM glucose for 24 h. Detritiation of [2-3H]glucose and [5-3H]glucose in 1 mM glucose islets was normal, suggesting that glucose transport and phosphorylation and all enzymes of glycolysis were not down-regulated in the incapacitated islets. 14CO2 formation from [U-14C]glucose and [6-14C]glucose was inhibited up to 80% and 14CO2 from methyl succinate was inhibited up to 60%, indicating that down-regulation at (a) mitochondrial site(s) might explain the incapacitated insulin release. 14CO2 formation from [3,4-14C]glucose (which becomes [1-14C]pyruvate) was decreased, indicating that the reaction catalyzed by pyruvate dehydrogenase was down-regulated. This decrease, however, was not as large as the decreases in 14CO2 formation from [U-14C]glucose, [2-14C]glucose (which becomes [2-14C]pyruvate), or [6-14C]glucose (which becomes [3-14C]pyruvate), indicating that other reactions were also down-regulated. 14CO2 formation from [1-14C]glucose was inhibited less than that from [6-14C]glucose in the incapacitated islets (34 vs 54%) and these rates indicated that flux of glucose through the pentose phosphate pathway was increased in the incapacitated islet, such that 29% (0.4 nmol of 1.4 glucose/100 islets/90 min) was metabolized via this pathway in the incapacitated islet but only 3.4% (0.1 of 2.9 nmol glucose/100 islets/90 min) was metabolized via the pentose pathway in the 20 mM glucose islets. With rates of 14CO2 evolved from glucose labeled at C2 and C6 and from methyl succinate labeled at C1 + C4 and C2 + C3 the 14CO2 ratio formula was used to calculate the ratios of carboxylated and decarboxylated pyruvate. Roughly equal amounts of pyruvate entered the citric acid cycle by each route in islets maintained for 24 h at 1, 5, or 20 mM glucose. The results indicate that decarboxylation and carboxylation of pyruvate were about equally suppressed in incapacitated islets and that direct inhibition of reactions of the cycle was unlikely. This is consistent with evidence which indicates that down-regulation of both pyruvate carboxylase and pyruvate dehydrogenase occurs in incapacitated islets, i.e., under long-term conditions that modify amounts of enzymes (MacDonald et al., 1991, J. Biol. Chem. 266, 22392-22397).(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗
PubMed1995

Pentose cycling and the distribution of 13C in trehalose during glucogenesis from 13C-labelled substrates in an insect.

Redistribution of 13C in trehalose (Tre) due to pentose cycling was observed in vivo in Manduca sexta during glucogenesis from [3-13C]alanine (Ala) and [2-13C]glycerol (Gly). The extent of cycling was affected by dietary composition. Larvae maintained on a low-carbohydrate diet (LCD) exhibited approximately 13% cycling, while those on a complete-balanced diet (CBD) or low-fat diet (LFD) displayed much higher rates of cycling. Significant incorporation of 13C via reversal of the non-oxidative phase was evident on all diets but was greatest on the CBD and LFD. In contrast to conclusions from previous studies with insects, the present results indicate that under normal conditions the pentose pathway is not the principal source of triose phosphates for oxidative catabolism during larval development.

Animals↗
PubMed1987

Inhibition of phosphoglucose isomerase allozymes from the wing polymorphic waterstrider, Limnoporus canaliculatus, by pentose shunt metabolites.

Inhibition of phosphoglucose isomerase (PGI) allozymes from the wing-polymorphic waterstrider, Limnoporus canaliculatus, by three pentose-shunt metabolites was studied at several different temperatures. This was done to determine if the allozymes exhibited a differential ability to participate in lipid biosynthesis via differential partitioning of carbon flux through the pentose shunt versus glycolysis. 6-Phosphogluconate and erythrose-4-phosphate proved to be strong competitive inhibitors of PGI, while sedoheptulose-7-phosphate was a very weak inhibitor. The PGI allozymes from L. canaliculatus were differentially inhibited by 6-phosphogluconate at two of the three temperatures studied. However, this property does not appear to be an adaptive difference between the allozymes but, rather, a correlated effect resulting from variation in substrate binding. Estimates of reaction rates for the allozymes indicate that the differences in inhibition result in no detectable differences in reaction velocities. Thus, no evidence in support of the hypothesis that PGI allozymes from Limnoporus canaliculatus were adapted to function in different metabolic capacities via differential inhibition was obtained in this study. However, the importance of this characteristic in allozymic adaptation in natural populations remains an open question.

Adaptation, Physiological↗
PubMed1978

Stimulation of myocardial adenine nucleotide biosynthesis by pentoses and pentitols.

In rats, pentoses and pentitols, intravenously injected in a single dose of 100 mg/kg, induced a considerable enhancement of the available pool of 5-phosphoribosyl-1-pyrophosphate and of the rate of adenine nucleotide biosynthesis in the heart, but not in liver and kidney. De novo synthesis of adenine nucleotides not detectable in skeletal muscle of normal rats became measurable after application of ribose. The stimulatory effect of isoproterenol on myocardial adenine nucleotide biosynthesis could be further potentiated by ribose and xylitol, but not by glucose. The isoproterenol-induced decrease of cardiac adenine nucleotide concentrations could be almost completely prevented by repeated administrations of ribose. Thus, pentoses and pentitols in combination with beta-receptor stimulation markedly and quite specifically enhance adenine nucleotide biosynthesis in the rat heart. The results indicate that the increase in the available pool of 5-phosphoribosyl-1-pyrophosphate is an important factor for the enhancement of cardiac adenine nucleotide biosynthesis. Moreover, the availability of 5-phosphoribosyl-1-pyrophosphate and the rate of de novo synthesis of adenine nucleotides in the heart seem to be limited by the flow through the hexose monophosphate shunt.

Adenine Nucleotides↗
PubMed1996

Mutants that show increased sensitivity to hydrogen peroxide reveal an important role for the pentose phosphate pathway in protection of yeast against oxidative stress.

We have isolated several mutants of Saccharomyces cerevisiae that are sensitive to oxidative stress in a screen for elevated sensitivity to hydrogen peroxide. Two of the sixteen complementation groups obtained correspond to structural genes encoding enzymes of the pentose phosphate pathway. Allelism of the pos10 mutation (POS for peroxide sensitivity) to the zwf1/met1 mutants in the structural gene for glucose 6-phosphate dehydrogenase was reported previously. The second mutation, pos18, was complemented by transformation with a yeast genomic library. The open reading frame of the isolated gene encodes 238 amino acids. No detectable ribulose 5-phosphate epimerase activity was found in the pos18 mutant, suggesting that the corresponding structural gene is affected in this mutant. For that reason the gene was renamed RPE1 (for ribulose 5-phosphate epimerase). RPE1 was localized to chromosome X. The predicted protein has a molecular mass of 25966 Daltons, a codon adaptation index (CAI) of 0.32, and an isoelectric point of 5.82. Database searches revealed 32 to 37% identity with ribulose 5-phosphate epimerases of Escherichia coli, Rhodospirillum rubrum, Alcaligenes eutrophus and Solanum tuberosum. We have characterized RPE1 by testing enzyme activities in rpe1 deletion mutants and in strains that overexpress RPE1, and compared the hydrogen peroxide sensitivity of rpe1 mutants to that of other mutants in the pentose phosphate pathway. Interestingly, all mutants tested (glucose 6-phosphate dehydrogenase, gluconate 6-phosphate dehydrogenase, ribulose 5-phosphate epimerase, transketolase, transaldolase) are sensitive to hydrogen peroxide.

3-Isopropylmalate Dehydrogenase↗
PubMed1995

Genetics of pentose-phosphate pathway enzymes of Escherichia coli K-12.

The pentose-phosphate pathway of Escherichia coli K-12, in addition to its role as a route for the breakdown of sugars such as glucose or pentoses, provides the cell with intermediates for the anabolism of amino acids, vitamins, nucleotides, and cell wall constituents. Through its oxidative branch, it is a major source of NADPH. The expression of the gene for NADP-dependent 6-phosphogluconate dehydrogenase (gnd) is regulated by the growth rate in E. coli. The recently identified gene for ribulose-5-phosphate 3-epimerase (rpe) is part of a large operon that comprises among other genes for the biosynthesis of aromatic amino acids. In recent years, genes for all enzymes of the pathway have been cloned and sequenced. Isoenzymes have been found for transketolase (genes tktA and tktB), ribose-5-phosphate isomerase (rpiA and rpiB) and transaldolase (talA and talB).

Amino Acid Sequence↗
PubMed1999

The activity of the pentose phosphate pathway is increased in response to oxidative stress in Alzheimer's disease.

In order to assess the integrity of antioxidant enzymes in Alzheimer's disease, the activities of glutathione peroxidase, glutathione reductase and two enzymes of the pentose phosphate pathway (glucose-6-phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase) were determined in three regions of postmortem neocortex of controls and subjects with Alzheimer's disease. The activities of glutathione peroxidase and glutathione reductase were unaffected in Alzheimer's disease. By contrast, there was a selective increase in the activities of glucose-6-phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase in the inferior temporal cortex of Alzheimer subjects. These changes negatively correlated with the Fe2+/ascorbate-induced lipid peroxidation which (in a previous study of the same subjects) was also found to be selectively elevated in the inferior temporal cortex. Increased activity of the pentose phosphate pathway probably occurs in response to increased prooxidant activity since both glucose-6-phosphate and 6-phosphonogluconate inhibited H2O2-induced lipid peroxidation in a concentration dependant fashion (IC50 = 504 +/- 105 microM and 88 +/- 12 microM, respectively). Together, these data suggest that not only is oxidative stress a feature of Alzheimer's disease, but also that it occurs because of increased prooxidant activity rather than a diminished antioxidant capacity.

Aged↗
PubMed1989

Prostaglandin E2 and alpha 2 adrenoceptor agonists inhibit the pentose phosphate shunt in pancreatic islets.

Glucose utilization in isolated pancreatic islets of the rat was inhibited by prostaglandin (PG) E2 and the alpha 2 adrenoceptor agonist, clonidine, to a similar extent; other prostaglandins did not affect glucose utilization. Islet oxidation of [1-14C]glucose and [6-14C]glucose demonstrated that the pentose phosphate shunt was inhibited by PGE2 and clonidine. Pertussis toxin antagonizes the effects of clonidine and PGE2 on total glucose utilization and pentose phosphate shunt activity. The results suggest that PGE2 and alpha 2 adrenoceptor agonists may regulate glucose metabolism through similar transduction mechanisms, and that a guanine nucleotide binding regulatory (G) protein modulates certain metabolic effects of prostaglandins and adrenergic agonists.

Adrenergic alpha-Agonists↗
PubMed1985

Identification and measurement of D-glycero D-ido octulose 1,8-bisphosphate: D-altro-heptulose 7-phosphotransferase enzyme in tissues with L-type pentose phosphate pathway activity.

The enzyme D-glycero D-ido octulose 1,8-bisphosphate:D-altro-heptulose 7-phosphotransferase (abbreviated to phosphotransferase, PT) catalyses the transfer of the phosphate ester group at C-1 between altro-heptulose (sedoheptulose) and octulose phosphate intermediates of the L-type pentose pathway. Using synthetically prepared and 14C-labelled octulose mono- and bisphosphates, two methods are described for the measurement of the catalytic capacity of the PT reaction operating in both the "forward" and "reverse" modes of L-type pentose pathway operation. PT activity was found in normal, regenerating and foetal rat liver, rat heart, rat epididymal fat pad, rat kidney, brain and skeletal muscle, extracts of C. fusca, pea leaf and a variety of tumour tissues. The highest activity of the enzyme was found in the neoplasms. The Michaelian kinetic constants, temperature and pH optima for the reaction of the enzyme from rat liver together with an assortment of its substrate specificities have been determined. Vanadate anion was found to inhibit the enzyme and the pattern of inhibition suggests that the PT may act by a sequential mechanism. Neither arabinose 5-phosphate nor inorganic phosphate showed any effect on the catalytic activity of the PT enzyme in liver.

Animals↗
PubMed1993

Effect of dehydroepiandrosterone on pentose phosphate pathway activity in the rat colon.

1. The effects of fasting and fasting followed by refeeding on the activities of the oxidative pentose pathway (OPP) and the non-oxidative pentose pathway (NOPP) were estimated by the rate of production of 14CO2 from [1-14C] glucose in isolated rat colonocytes, and the production of hexose 6-phosphates from ribose 5-phosphate in rat colonic cytosols, respectively. 2. The OPP activity in colonocytes from rats in the fasted state was 50% lower when compared to colonocytes from rats refed after a fast. This indicated induction of the rate-limiting enzyme of the OPP, glucose 6-P dehydrogenase (G6-PDH) in the latter instance. No effect on the maximal catalytic activity of the enzymes of the NOPP was seen in colonocytes from rats refed after a fast compared with colonocytes from rats in the fasted state. 3. Isolated colonocytes obtained from the distal colon of rats refed after a fast, showed a significant decrease (30%) in OPP activity when incubated with 50 microM dehydroepiandrosterone (DHEA). A similar degree of inhibition was seen with 10 mM butyrate (P < 0.05). In contrast, using colonic cytosols, both DHEA and butyrate had no effect on the maximal catalytic activity of the NOPP. 4. Intraperitoneal injection (i.p.) of DHEA in rats refed after a fast showed a significant increase in the maximal catalytic activity of the NOPP in the distal colon (46%; P < 0.05). A similar elevation in the maximal catalytic activity of the NOPP was seen in the distal colon of DHEA treated pair-fed rats (43%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Gluconate metabolism in germinated spores of Bacillus megaterium QM B1551: primary roles of gluconokinase and the pentose cycle.

The metabolic pathway of gluconate, a major product of glucose metabolism during spore germination, was investigated in Bacillus megaterium QM B1551. Compared to the parent, mutant spores lacking gluconokinase could not metabolize gluconate, whereas the revertant simultaneously restored the enzyme activity and the ability to metabolize it, indicating that gluconokinase was solely responsible for the onset of gluconate metabolism. To identify a further metabolic route for gluconate, we determined 14C yields in acetate and CO2 formed from [14C]gluconate, and found that experimental ratios of 14CO2/[14C]acetate obtained from [2-14C]gluconate and [3,4-14C]gluconate were not compatible with the ratios predicted from the Entner-Doudoroff pathway. In contrast, when CO2 release caused by recycling (approx. 30%) was corrected, the ratios almost agreed with those from the pentose cycle. Comparison of specific radioactivities in acetate also supported the conclusion that gluconate was metabolized via the pentose cycle, subsequently metabolized via the Embden-Meyerhof pathway, and finally degraded to acetate and CO2 without a contribution by the Krebs cycle.

Acetates↗
PubMed2003

Paraquat and menadione exposure of rainbow trout (Oncorhynchus mykiss)--studies of effects on the pentose-phosphate shunt and thiamine levels in liver and kidney.

Possible xenobiotic interactions with thiamine were studied in salmonid fish, by repeatedly injecting two model substances, paraquat and menadione, into juvenile rainbow trout (Oncorhynchus mykiss). These two substances were chosen because of their well-known ability to redox-cycle and cause depletion of NADPH in several biological systems. Depletion of NADPH increases metabolism through the pentose-phosphate shunt and may thereby increase the need for thiamine diphosphate by heightened transketolase activity. A special food was produced with lower thiamine content than commercial food, usually enriched with thiamine, which could mask an effect on the thiamine level. After 9 weeks of exposure, glucose-6-phosphate dehydrogenase, transketolase, glutathione reductase and ethoxyresorufin O-deethylase were analysed in liver and kidney cellular sub-fractions as well as analysis of total thiamine concentrations in liver, kidney and muscle. The results showed that paraquat caused a large increase in hepatic glutathione reductase activity and induced hepatic glucose-6-phosphate dehydrogenase activity, i.e., the rate-limiting enzyme in the oxidative part of the pentose-phosphate shunt. Despite this paraquat exposure did not affect transketolase activity and total thiamine concentration.

Animals↗
PubMed2000

Non-steroidal anti-inflammatory drugs and apoptosis in the gastrointestinal tract: potential role of the pentose phosphate pathways.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs, primarily for treatment of arthritis. NSAIDs can have two effects independent of their anti-inflammatory action. In the stomach and small bowel long term NSAID consumption can lead to ulceration, whereas in the colon NSAID use can regress existing tumours. In this review, we hypothesise that NSAID-induced damage occurs predominantly by promoting apoptosis, involving a number of mechanisms depending on the type and the redox state of the cell. In addition to inhibiting cyclooxygenase (COX) activity, this includes interfering with glucose metabolism through both arms of the pentose phosphate pathways and energy production via glycolysis and oxidative phosphorylation. Shifting the cellular balance from proliferation to apoptosis is probably the most important outcome by which NSAIDs exhibit their differing actions. Understanding how these different pathways can be reconciled and their contribution to the balance between cell birth and cell death is the challenge for the future. The pentose phosphate pathways may provide a pivotal point for understanding links between factors which alter proliferative activity (e.g. COXs), provide energy metabolism (particularly aerobic and anaerobic metabolism of glucose), and change the redox state of the cell leading to apoptosis.

Animals↗
PubMed2000

Cells overexpressing fructose-2,6-bisphosphatase showed enhanced pentose phosphate pathway flux and resistance to oxidative stress.

Changes in the content of fructose-2,6-bisphosphate, a modulator of glycolytic flux, also affect other metabolic fluxes such as the non-oxidative pentose phosphate pathway. Since this is the main source of precursors for biosynthesis in proliferating cells, PFK-2/FBPase-2 has been proposed as a potential target for neoplastic treatments. Here we provide evidence that cells with a low content of fructose-2,6-bisphosphate have a lower energy status than controls, but they are also less sensitive to oxidative stress. This feature is related to the activation of the oxidative branch of the pentose phosphate pathway and the increased production of NADPH.

Animals↗
PubMed1988

Economy of design in metabolic pathways: further remarks on the game of the pentose phosphate cycle.

Sugar rearrangement in the pentose phosphate cycle and other related pathways were previously analysed by abstraction to a mathematical game of optimization based on certain hypotheses concerning enzymatic mechanisms of living cells (Meléndez-Hevia & Isidoro, 1985, J. theor. Biol. 117, 251-263). The solution of that problem shows that the metabolic pathway, as occurs in cells, is the simplest solution of the operative problem. However, in that work, only the number of carbons in every sugar was considered. In the present paper, all structural features of the sugars and reaction mechanisms are taken into consideration, and the problem is again considered by abstraction to a mathematical model which includes all structural features of the sugars as well as all structural requirements of the enzymes in the hypotheses of the mechanisms. As in the above-mentioned paper, the hypothesis of simplicity is also imposed in order to achieve the objective (to convert six ribulose 5-phosphate into five glucose 6-phosphate) in the least number of steps (or with the least number of free intermediates), and the least number of carbons in the intermediates. It is concluded that the optimal, or simplest, solution of this problem is the same procedure as that occurring in living cells. The Calvin cycle in photosynthesis and the "L-type" of the pentose phosphate cycle are also analysed arriving at similar conclusions in both cases. These results suggest some reflections about the logic in the design of metabolic pathways, and the possible role of the hypothesis of simplicity in cell evolution.

Biological Evolution↗
PubMed2004

Effects of long-term exposure to Cu2+ and Cd2+ on the pentose phosphate pathway dehydrogenase activities in the ovary of adult Bufo arenarum: possible role as biomarker for Cu2+ toxicity.

The effects of copper and cadmium on metabolism through the pentose phosphate pathway were evaluated in Bufo arenarum toad ovary. The effects of the two metals on dehydrogenases from this pathway were evaluated by three experiments: (1) in samples obtained from control females with addition of the metals to the reaction mixture (in vitro), (2) in samples obtained from control females and after long-term exposure of females to 4 and 100 microg/L of Cu or Cd in the incubation media (in vitro after exposure to the metals in vivo), and (3) 14CO2 production through the pentose phosphate pathway was evaluated after [U-14C]glucose microinjection on ovulated oocytes (in vivo after microinjection of the metals). Results from (1) evidenced inhibition of both enzyme activities but only above 1.5 mM Cu and Cd added to the reaction mixture. In (2) both glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities decreased in samples from the ovaries of females exposed in vivo to Cu, in a concentration-dependent manner (up to 90% in females exposed to 100 microg/L Cu: 2.12 +/- 1.57 NADPH micromol/min microg protein x 10(-5) vs 19.97 +/- 8.54 in control females). Cd treatment of the toads only rendered an inhibitory effect on 6-phosphogluconate dehydrogenase activity after exposure to 4 microg/L of the bivalent cation. (3) In vivo 14CO2 evolution significantly decreased in oocytes coinjected with 6.3 x 10(-3) mM Cu (calculated intracellular final concentration of the metal injected) and radioactive glucose. Cu and Cd concentration in samples from exposed females were always under detection limit by particle-induced X-ray emission. The results presented here are in agreement with a role for both glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities determination as biomarkers of effect and exposure for Cu but not for Cd toxicity.

Animals↗