scholarly journals DHEA-Mediated Inhibition of the Pentose Phosphate Pathway Alters Oocyte Lipid Metabolism in Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4835-4844 ◽  
Author(s):  
Patricia T. Jimenez ◽  
Antonina I. Frolova ◽  
Maggie M. Chi ◽  
Natalia M. Grindler ◽  
Alexandra R. Willcockson ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Negative Impact ◽  
Polycystic Ovary ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pentose Phosphate ◽  
Polycystic Ovaries ◽  
Estrous Cycles ◽  
Hormone Levels ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Women with polycystic ovary syndrome (PCOS) and hyperandrogenism have altered hormone levels and suffer from ovarian dysfunction leading to subfertility. We have attempted to generate a model of hyperandrogenism by feeding mice chow supplemented with dehydroepiandrosterone (DHEA), an androgen precursor that is often elevated in women with PCOS. Treated mice had polycystic ovaries, low ovulation rates, disrupted estrous cycles, and altered hormone levels. Because DHEA is an inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway, we tested the hypothesis that oocytes from DHEA-exposed mice would have metabolic disruptions. Citrate levels, glucose-6-phosphate dehydrogenase activity, and lipid content in denuded oocytes from these mice were significantly lower than controls, suggesting abnormal tricarboxylic acid and pentose phosphate pathway metabolism. The lipid and citrate effects were reversible by supplementation with nicotinic acid, a precursor for reduced nicotinamide adenine dinucleotide phosphate. These findings suggest that elevations in systemic DHEA can have a negative impact on oocyte metabolism and may contribute to poor pregnancy outcomes in women with hyperandrogenism and PCOS.

scholarly journals Catalysis of pentose phosphate pathway reactions by cytoplasmic fractions from muscle, uterus and liver of the rat, and the presence of a reduced nicotinamide–adenine dinucleotide phosphate–triose phosphate oxidoreductase in rat muscle

1974 ◽  
Vol 138 (1) ◽  
pp. 71-76 ◽  
Author(s):  
Terry Wood
Keyword(s):  
Pentose Phosphate Pathway ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pentose Phosphate ◽  
Hexose Monophosphate ◽  
Triose Phosphate ◽  
Phosphogluconate Dehydrogenase ◽  
Rat Muscle ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

1. The enzymes of the pentose phosphate pathway were assayed in supernatant fractions from rat muscle, liver and uterus. 2. On incubation of ribose 5-phosphate with uterus and liver supernatants, triose phosphate, sedoheptulose 7-phosphate and hexose monophosphate accumulated. 3. When a muscle supernatant was used, glycerol 3-phosphate instead of triose phosphate appeared and there was a negligible accumulation of hexose monophosphate. 4. Hexose monophosphate production from ribose 5-phosphate was also followed by measuring NADP+ reduction in the presence of an excess of phosphoglucose isomerase, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. 5. With a muscle supernatant, NADPH was reoxidized as rapidly as it was formed owing to the presence of a NADPH–triose phosphate oxidoreductase. 6. A modification of the pentose phosphate pathway in skeletal muscle incorporating this enzyme is proposed.

scholarly journals Theoretical Analysis of the Built-in Metabolic Pathway Effect on the Metabolism of Erythrocyte-Bioreactors That Neutralize Ammonium

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 36
Author(s):  
Evgeniy Protasov ◽  
Larisa Koleva ◽  
Elizaveta Bovt ◽  
Fazoil I. Ataullakhanov ◽  
Elena Sinauridze
Keyword(s):  
Steady State ◽  
Glutamate Dehydrogenase ◽  
Pentose Phosphate Pathway ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pentose Phosphate ◽  
Nicotinamide Adenine ◽  
Limiting Factor ◽  
Glutamate Dehydrogenase Activity ◽  
Reduced Nicotinamide Adenine Dinucleotide

The limitations of the efficiency of ammonium-neutralizing erythrocyte-bioreactors based on glutamate dehydrogenase and alanine aminotransferase reactions were analyzed using a mathematical model. At low pyruvate concentrations in the external medium (below about 0.3 mM), the main limiting factor is the rate of pyruvate influx into the erythrocyte from the outside, and at higher concentrations, it is the disappearance of a steady state in glycolysis if the rate of ammonium processing is higher than the critical value (about 12 mM/h). This rate corresponds to different values of glutamate dehydrogenase activity at different concentrations of pyruvate in plasma. Oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) by glutamate dehydrogenase decreases the fraction of NADPH in the constant pool of nicotinamide adenine dinucleotide phosphates (NADP + NADPH). This, in turn, activates the pentose phosphate pathway, where NADP reduces to NADPH. Due to the increase in flux through the pentose phosphate pathway, stabilization of the ATP concentration becomes impossible; its value increases until almost the entire pool of adenylates transforms into the ATP form. As the pool of adenylates is constant, the ADP concentration decreases dramatically. This slows the pyruvate kinase reaction, leading to the disappearance of the steady state in glycolysis.

scholarly journals The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (3) ◽  
pp. 259-274 ◽  
Author(s):  
Rachit Badolia ◽  
Dinesh K.A. Ramadurai ◽  
E. Dale Abel ◽  
Peter Ferrin ◽  
Iosif Taleb ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pentose Phosphate Pathway ◽  
Carbon Metabolism ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Left Ventricular ◽  
Pentose Phosphate ◽  
Myocardial Recovery ◽  
Mechanical Unloading ◽  
Reduced Nicotinamide Adenine Dinucleotide

Background: Significant improvements in myocardial structure and function have been reported in some patients with advanced heart failure (termed responders [R]) following left ventricular assist device (LVAD)–induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our previous work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation through the tricarboxylic acid cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and 1-carbon metabolism, which may mediate myocardial recovery in R. Methods: We prospectively obtained paired left ventricular apical myocardial tissue from nonfailing donor hearts as well as R and nonresponders at LVAD implantation (pre-LVAD) and transplantation (post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. Results: Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and 1-carbon metabolism in post-LVAD R (post-R) as compared with post-LVAD nonresponders (post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (1-carbon metabolism) were also decreased in Post-R. Furthermore, post-R had significantly higher reduced nicotinamide adenine dinucleotide phosphate levels, reduced reactive oxygen species levels, improved mitochondrial density, and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and 1-carbon metabolism that correlated with the observed myocardial recovery. Conclusions: The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and 1-carbon metabolism, which could contribute to cardioprotection by generating reduced nicotinamide adenine dinucleotide phosphate to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial effect of glycolysis induction during the recovery of failing human hearts after mechanical unloading.

NADPH Producing Enzymes as Promising Drug Targets for Chagas Disease

2019 ◽  
Vol 26 (36) ◽  
pp. 6564-6571
Author(s):  
Artur T. Cordeiro
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
New Drugs ◽  
Trypanosomatid Parasites ◽  
Drug Target Validation ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) is a cofactor used in different anabolic reactions, such as lipid and nucleic acid synthesis, and for oxidative stress defense. NADPH is essential for parasite growth and viability. In trypanosomatid parasites, NADPH is supplied by the oxidative branch of the pentose phosphate pathway and by enzymes associated with the citric acid cycle. The present article will review recent achievements that suggest glucose-6-phosphate dehydrogenase and the cytosolic isoform of the malic enzyme as promising drug targets for the discovery of new drugs against Trypanosoma cruzi and T. brucei. Topics involving an alternative strategy in accelerating T. cruzi drug-target validation and the concept of drug-target classification will also be revisited.

scholarly journals Minireview: Hexose-6-Phosphate Dehydrogenase and Redox Control of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2539-2543 ◽  
Author(s):  
Kylie N. Hewitt ◽  
Elizabeth A. Walker ◽  
Paul M. Stewart
Keyword(s):  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hydroxysteroid Dehydrogenase ◽  
Pentose Phosphate ◽  
Intact Cells ◽  
The Metabolic Syndrome ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Abstract Hexose-6-phosphate dehydrogenase (H6PDH) is a microsomal enzyme that is able to catalyze the first two reactions of an endoluminal pentose phosphate pathway, thereby generating reduced nicotinamide adenine dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is distinct from the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PDH), using a separate pool of NAD(P)+ and capable of oxidizing several phosphorylated hexoses. It has been proposed to be a NADPH regenerating system for steroid hormone and drug metabolism, specifically in determining the set point of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, the enzyme responsible for the activation and inactivation of glucocorticoids. 11β-HSD1 is a bidirectional enzyme, but in intact cells displays predominately oxo-reductase activity, a reaction requiring NADPH and leading to activation of glucocorticoids. However, in cellular homogenates or in purified preparations, 11β-HSD1 is exclusively a dehydrogenase. Because H6PDH and 11β-HSD1 are coexpressed in the inner microsomal compartment of cells, we hypothesized that H6PDH may provide 11β-HSD1 with NADPH, thus promoting oxo-reductase activity in vivo. Recently, several studies have confirmed this functional cooperation, indicating the importance of intracellular redox mechanisms for the prereceptor control of glucocorticoid availability. With the increased interest in 11β-HSD1 oxo-reductase activity in the pathogenesis and treatment of several human diseases including insulin resistance and the metabolic syndrome, H6PDH represents an additional novel candidate for intervention.

scholarly journals Annurca Apple Polyphenols Ignite Keratin Production in Hair Follicles by Inhibiting the Pentose Phosphate Pathway and Amino Acid Oxidation

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1406 ◽  
Author(s):  
Nadia Badolati ◽  
Eduardo Sommella ◽  
Gennaro Riccio ◽  
Emanuela Salviati ◽  
Dimitri Heintz ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Hair Growth ◽  
High Resolution Mass Spectrometry ◽  
Negative Impact ◽  
Adult Population ◽  
Pentose Phosphate ◽  
Hair Follicles ◽  
Acid Oxidation ◽  
Healthy Human ◽  
Nucleotide Synthesis

Patterned hair loss (PHL) affects around 50% of the adult population worldwide. The negative impact that this condition exerts on people’s life quality has boosted the appearance of over-the-counter products endowed with hair-promoting activity. Nutraceuticals enriched in polyphenols have been recently shown to promote hair growth and counteract PHL. Malus pumila Miller cv. Annurca is an apple native to Southern Italy presenting one of the highest contents of Procyanidin B2. We have recently shown that oral consumption of Annurca polyphenolic extracts (AAE) stimulates hair growth, hair number, hair weight and keratin content in healthy human subjects. Despite its activity, the analysis of the molecular mechanism behind its hair promoting effect is still partially unclear. In this work we performed an unprecedented metabolite analysis of hair follicles (HFs) in mice topically treated with AAE. The metabolomic profile, based on a high-resolution mass spectrometry approach, revealed that AAE re-programs murine HF metabolism. AAE acts by inhibiting several NADPH dependent reactions. Glutaminolysis, pentose phosphate pathway, glutathione, citrulline and nucleotide synthesis are all halted in vivo by the treatment of HFs with AAE. On the contrary, mitochondrial respiration, β-oxidation and keratin production are stimulated by the treatment with AAE. The metabolic shift induced by AAE spares amino acids from being oxidized, ultimately keeping them available for keratin biosynthesis.

scholarly journals Equine Glucose-6-phosphate Dehydrogenase Deficiency

1994 ◽  
Vol 31 (5) ◽  
pp. 518-527 ◽  
Author(s):  
S. L. Stockham ◽  
J. W. Harvey ◽  
D. A. Kinden
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
G6pd Deficiency ◽  
Dehydrogenase Deficiency ◽  
Reduced Glutathione ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Electron Microscopic ◽  
Transmission Electron ◽  
Transmission Electron Microscopic ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a well-characterized X-linked inherited disorder in humans but has not been reported in horses. We describe a persistent hemolytic anemia and hyperbilirubinemia due to a severe G6PD deficiency in an American Saddlebred colt. Other abnormalities in the colt's erythrocytes as compared with those of healthy horses ( n = 22–35) included increased activities of hexokinase and pyruvate kinase, decreased concentrations of reduced glutathione and reduced nicotinamide adenine dinucleotide phosphate (NADP), and increased concentration of oxidized NADP. Morphologic abnormalities included eccentrocytosis, pyknocytosis, anisocytosis, macrocytosis, and increased number of Howell-Jolly bodies. Scanning and transmission electron microscopic examinations revealed that eccentrocytes had contracted to spherical regions and thin collapsed regions. Eccentrocytes were more electron dense than were normal erythrocytes when examined by transmission electron microscopy. When exposed to acetylphenylhydrazine, erythrocytes from the G6PD-deficient colt produced more and smaller Heinz bodies than did erythrocytes from normal horses. Abnormalities in the colt's dam included presence of eccentrocytes and pyknocytes; her average erythrocyte G6PD activity was slightly below the range of reference values.

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