Regulation of pentose phosphate pathway dehydrogenases by NADP+/NADPH ratios

Holten, Darold; Procsal, Dana A.; Chang, Hsiao-Lin

doi:10.1016/0006-291x(76)91164-5

Cited by 68 publications

(31 citation statements)

References 15 publications

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“…This agrees with the depletion of NADPH levels [14] as well as with the observations in a galactose model [50] and favours activation of the pentose phosphate pathway regenerating reducing equivalents (NAD-PH) for aldose reductase [51]. The failure of dl-a-lipoic acid to affect the redox state of free cytosolic NADP-couple is consistent with the absence of changes in sorbitol pathway metabolites, and implies a similar rate of use of NADPH by aldose reductase in DL-a-lipoic acid treated and untreated groups.…”

Section: Discussionsupporting

confidence: 89%

Diabetes-induced changes in lens antioxidant status, glucose utilization and energy metabolism: effect of DL-?-lipoic acid

et al. 1998

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According to the data of the National Diabetes Data Group [1], the prevalence of cataracts ± one of the major ocular disorders in patients with diabetes mellitus ± is at least 50 % higher in both Type I (insulindependent) diabetes mellitus and Type II (non-insulin-dependent) diabetes than in corresponding agematched non-diabetic subjects. Sugar cataractogenesis is initiated by osmotic stress caused by intralenticular accumulation of polyols produced by the enzyme aldose reductase [2±6]. Although growing evidence indicates the key role of an osmotic mechanism in the sequelae of biochemical and morphological chan- Diabetologia (1998) Summary The study was aimed at evaluating changes in lens antioxidant status, glucose utilization, redox state of free cytosolic NAD(P)-couples and adenine nucleotides in rats with 6-week streptozotocin-induced diabetes, and to assess a possibility of preventing them by dl-a-lipoic acid. Rats were divided into control and diabetic groups treated with and without dl-a-lipoic acid (100 mg × kg body weight ±1 × day ±1 , i. p.). The concentrations of glucose, sorbitol, fructose, myo-inositol, oxidized glutathione, glycolytic intermediates, malate, a-glycerophosphate, and adenine nucleotides were assayed in individual lenses spectrofluorometrically by enzymatic methods, reduced glutathione and ascorbate ± colorimetrically, and taurine by HPLC. Free cytosolic NAD + :NADH and NADP + :NADPH ratios were calculated from the lactate dehydrogenase and malic enzyme systems. Sorbitol pathway metabolites were found to increase, and antioxidant concentrations were reduced in diabetic rats compared with controls. The profile of glycolytic intermediates (increase in glucose 6-phosphate and fructose 6-phosphate, decrease in fructose1,6-diphosphate, increase in dihydroxyacetone phosphate, 3-phosphoglycerate, phosphoenolpyruvate, pyruvate, and no change in lactate), and 5.9-fold increase in a-glycerophosphate suggest diabetes-induced inhibition of glycolysis. Free cytosolic NAD + :-NADH ratios, ATP levels, ATP/ADP´inorganic phosphate (P i ), and adenylate charge were reduced in diabetic rats while free cytosolic NADP + :NADPH ratios were elevated. Diabetes-induced changes in the concentrations of antioxidants, key glycolytic intermediates, free cytosolic NAD + :NADH ratios, and energy status were partially prevented by dl-a-lipoic acid, while sorbitol pathway metabolites and free cytosolic NADP + :NADPH ratios remained unaffected. In conclusion, diabetes-induced impairment of lens antioxidative defense, glucose intermediary metabolism via glycolysis, energy status and redox changes are partially prevented by dl-a-lipoic acid. The findings support the important role of oxidative stress in lens metabolic imbalances in diabetes. [Diabetologia (1998

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Section: Discussionsupporting

confidence: 89%

Diabetes-induced changes in lens antioxidant status, glucose utilization and energy metabolism: effect of DL-?-lipoic acid

et al. 1998

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“…By exclusion, we argue that oxidative flux rerouting is caused by either direct oxidation of G6PD, other unreported post-translational modifications, or allosteric interactions that affect its conformation and activity (Patra and Hay, 2014). A probable mechanism is direct inhibition by NADPH (Cho and Joshi, 1990;Holten et al, 1976;Ozer et al, 2001), which we could verify with own biochemical assays and is also consistent with the observed immediate drop in NADPH ( Figures 1E and S7A). Such a regulatory mechanism brings about a purely demand-driven regeneration of NADPH during acute stress, which engages without temporal delays.…”

Section: Model Of Immediate Ppp Activation Upon Oxidative Stresssupporting

confidence: 83%

“…Two key metabolites that could directly activate flux into oxidative PPP are NADPH as G6PD inhibitor (Cho and Joshi, 1990;Holten et al, 1976;Ozer et al, 2001) and 6PG as PGI inhibitor (Kahana et al, 1960;Tsuboi et al, 1971). To specifically assess the transient NADPH levels, we analyzed metabolite extracts prepared without the drying step, which affects redox-sensitive species.…”

Section: Model For Immediate Activation Of Oxidative Ppp Upon H 2 O 2mentioning

confidence: 99%

Acute Activation of Oxidative Pentose Phosphate Pathway as First-Line Response to Oxidative Stress in Human Skin Cells

et al. 2015

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Integrity of human skin is endangered by exposure to UV irradiation and chemical stressors, which can provoke a toxic production of reactive oxygen species (ROS) and oxidative damage. Since oxidation of proteins and metabolites occurs virtually instantaneously, immediate cellular countermeasures are pivotal to mitigate the negative implications of acute oxidative stress. We investigated the short-term metabolic response in human skin fibroblasts and keratinocytes to H2O2 and UV exposure. In time-resolved metabolomics experiments, we observed that within seconds after stress induction, glucose catabolism is routed to the oxidative pentose phosphate pathway (PPP) and nucleotide synthesis independent of previously postulated blocks in glycolysis (i.e., of GAPDH or PKM2). Through ultra-short (13)C labeling experiments, we provide evidence for multiple cycling of carbon backbones in the oxidative PPP, potentially maximizing NADPH reduction. The identified metabolic rerouting in oxidative and non-oxidative PPP has important physiological roles in stabilization of the redox balance and ROS clearance.

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“…Since NADPH is a competitive inhibitor with respect to both NADP+ and G6P, a rapid equilibrium random mechanism fits our data best. A similar mechanism has been proposed for G6PD from P. duponti, P. notatum (Malcolm & Shepherd, 1972), and Saccharomyces carlsbergensis (Holten et al, 1976). For G6PD from human, pig and rat liver an ordered mechanism has been deduced from inhibition studies (Levy, 1979).…”

Section: Discussionmentioning

confidence: 61%

Purification and characterization of glucose-6-phosphate dehydrogenase from Aspergillus niger and Aspergillus nidulans

Wennekes¹,

Goosen²,

Broek³

et al. 1993

Journal of General Microbiology

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~Glucose-6-phosphate dehydrogenase (G6PD; D-glucose &phosphate:NADP+ oxidoreductase, EC 1.1.1.49) has been purified from AspergiZZus nidulans and AspergiZZus niger by a combination of affinity and anion exchange chromatography. A 500-1000-fold purification was obtained and the final enzyme preparations were shown to be pure but not homogeneous. For both fungi the purified enzyme preparation gave two bands on native and denaturing gels. The catalytically active form is a multimer. The molecular mass of the monomers is 60 and 57 kDa for A. nidulms and 55 and 53 kDa for A , niger. Both enzymes exhibited strict specificity towards both substrates glucose 6-phosphate and NADP+. The A . niduZans and A . niger G6PD enzymes catalyse the conversion of glucose Gphosphate via a random order mechanism. Inhibition studies provided evidence for the physiological role of G6PD as producer of NADPH in both fungi.

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Regulation of pentose phosphate pathway dehydrogenases by NADP+/NADPH ratios

Cited by 68 publications

References 15 publications

Diabetes-induced changes in lens antioxidant status, glucose utilization and energy metabolism: effect of DL-?-lipoic acid

Diabetes-induced changes in lens antioxidant status, glucose utilization and energy metabolism: effect of DL-?-lipoic acid

Acute Activation of Oxidative Pentose Phosphate Pathway as First-Line Response to Oxidative Stress in Human Skin Cells

Purification and characterization of glucose-6-phosphate dehydrogenase from Aspergillus niger and Aspergillus nidulans

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