Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11beta-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.
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PMID:Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. 1285 76

Oxidative stress and the resulting change in cell redox state are proposed to contribute to pathogenic alterations in ion channels that underlie electrical remodeling of the diseased heart. The present study examined whether K(+) channel remodeling is controlled by endogenous oxidoreductase systems that regulate redox-sensitive cell functions. Diabetes was induced in rats by streptozotocin, and experiments were conducted after 3-5 wk of hyperglycemia. Spectrophotometric assays of ventricular tissue extracts from diabetic rat hearts revealed divergent changes in two major oxidoreductase systems. The thioredoxin (TRX) system in diabetic rat heart was characterized by a 52% decrease in TRX reductase (TRXR) activity from control heart (P < 0.05), whereas TRX activity was 1.7-fold greater than control heart (P < 0.05). Diabetes elicited similar changes in the glutaredoxin (GRX) system: glutathione reductase was decreased 35% from control level (P < 0.05), and GRX activity was 2.5-fold greater than in control heart (P < 0.05). The basal activity of glucose-6-phosphate dehydrogenase, which generates NADPH required by the TRX and GRX systems, was not altered by diabetes. Voltage-clamp studies showed that the characteristically decreased density of the transient outward K(+) current (I(to)) in isolated diabetic rat myocytes was normalized by in vitro treatment with insulin (0.1 microM) or the metabolic activator dichloroacetate (1.5 mM). The effect of these agonists on I(to) was blocked by inhibitors of glucose-6-phosphate dehydrogenase. Moreover, inhibitors of TRXR, which controls the reducing activity of TRX, also blocked upregulation of I(to) by insulin and dichloroacetate. These data suggest that K(+) channels underlying I(to) are regulated in a redox-sensitive manner by the TRX system and the remodeling of I(to) that occurs in diabetes may be due to decreased TRXR activity. We propose that oxidoreductase systems are an important repair mechanism that protects ion channels and associated regulatory proteins from irreversible oxidative damage.
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PMID:Redox regulation of Ito remodeling in diabetic rat heart. 1553 26

The effect of 3,4-di(OH)-phenylpropionic acid (L-phenylalanine methyl ester) amide (SL-1063), a synthetic derivative of 3,4-di(OH)-cinnamate, on the cholesterol metabolism and antioxidant enzyme system was examined in rats. Diets that included either SL-1063 (0.046%, w/w) or lovastatin (0.02%, w/w) as a supplement, plus 1 g cholesterol/100 g diet were fed to rats ad libitum for 5 weeks. The total plasma cholesterol and triglyceride levels were significantly lowered by the SL-1063 supplement compared to the control group. Meanwhile, the levels of plasma HDL-cholesterol and ratio of HDL-cholesterol/total cholesterol (%) were significantly higher in the SL-1063 group than in the control group. However, the lovastatin supplement did not affect the plasma lipid level. The hepatic cholesterol level and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity were significantly lowered in the lovastatin group compared to the SL-1063 group; however, the hepatic triglyceride level did not differ among the groups. The activity of hepatic acyl CoA: cholesterol acyltransferase (ACAT), the enzyme that catalyzes hepatic cholesterol esterification, was significantly lower in the lovastatin and SL-1063 groups than in the control group. Furthermore, the SL-1063 supplement elevated the excretion of fecal sterols. As regards the hepatic antioxidant enzyme system, the superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities were all significantly higher in the SL-1063 group compared to the control group, whereas only the GR activity was significantly increased by the lovastatin supplement. No marked difference in the GSH levels and glucose-6-phosphate dehydrogenase (G6PD) activities was observed among the groups. The levels of plasma and hepatic thiobarbituric acid reactive substances (TBARS) were lowered by the SL-1063 supplement compared to the control group. Accordingly, the current results suggest that SL-1063, a synthetic derivative of 3,4-di(OH)-cinnamate, is effective in lowering the plasma lipids and improving the antioxidant enzyme system.
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PMID:Effect of 3,4-di(OH)-cinnamate synthetic derivative on plasma and hepatic cholesterol level and antioxidant enzyme activities in high cholesterol-fed rats. 1554 4

In glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes, failure to maintain normal levels of reduced glutathione (GSH) due to decreased NADPH regeneration in the hexose monophosphate pathway results in acute hemolytic anemia following exposure to oxidative insults, such as ingestion of Vicia fava beans or use of certain drugs. GSH is a source of protection against oxidative attack, used by the selenium-dependent glutathione peroxidase (Se-GSH-Px)/reductase (GR) system to detoxify hydrogen peroxide and organic peroxides, provided that sufficient GSH is made available. In this study, Se-GSH-Px activity was analyzed in G6PD-deficient patients in the presence of reducing agents such as N-Acetyl cysteine, L-cysteine, and beta-mercaptoethanol. Se-GSH-Px activity was decreased in G6PD-deficient red blood cells (RBCs). N-Acetyl cysteine, L-cysteine, and beta-mercaptoethanol increased Se-GSH-Px activity in G6PD-deficient human erythrocytes, indicating that other reducing agents can be utilized to complement Se-GSH-Px activity in G6PD deficiency. Based on the increased susceptibility of G6PD-deficient patients to oxidative stress, the reported increase in Se-GSH-Px activity can facilitate the detoxification of reactive oxygen species.
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PMID:N-acetyl cysteine, L-cysteine, and beta-mercaptoethanol augment selenium-glutathione peroxidase activity in glucose-6-phosphate dehydrogenase-deficient human erythrocytes. 1559 86

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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity, the enzyme responsible for the activation and inactivation of glucocorticoids. 11beta-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, 11beta-HSD1 is exclusively a dehydrogenase. Because H6PDH and 11beta-HSD1 are coexpressed in the inner microsomal compartment of cells, we hypothesized that H6PDH may provide 11beta-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 11beta-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.
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PMID:Minireview: hexose-6-phosphate dehydrogenase and redox control of 11{beta}-hydroxysteroid dehydrogenase type 1 activity. 1577 58

Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert active cortisol and inactive cortisone. 11 beta-HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11 beta-HSD1 (liver) is a bi-directional enzyme in cell homogenates, whereas in intact cells it typically displays oxo-reductase activity, generating cortisol from cortisone. We recently established that cortisone reductase deficiency is a digenic disease requiring mutations in both the gene encoding 11 beta-HSD1 and in the gene for a novel enzyme located within the lumen of the endoplasmic reticulum (ER), hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the co-factor required for oxo-reductase activity. Therefore, we hypothesized that H6PDH expression may be an important determinant of 11 beta-HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11 beta-HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11 beta-HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11 beta-HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11 beta-HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11 beta-HSD1 cDNA, transfection of an H6PDH siRNA reduced 11 beta-HSD1 oxo-reductase activity whilst simultaneously increasing 11 beta-HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11 beta-HSD1 oxo-reductase activity, independent of 11 beta-HSD1 mRNA levels. H6PDH expression increased 5.3-fold across adipocyte differentiation (P < 0.05) and was associated with a switch from 11 beta-HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11 beta-HSD1 oxo-reductase activity in intact cells. Through its interaction with 11 beta-HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.
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PMID:Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1. 1595 39

Flavonoids have been identified as the antidiabetic components in a number of traditional ethnic remedies. However, the mechanisms whereby these compounds exert their hypoglycemic and hypolipidemic action in type-2 diabetes have rarely been investigated. Therefore, this study investigated the effect of the flavonoids hesperidin and naringin on glucose and lipid regulation in C57BL/KsJ-db/db mice. Hesperidin and naringin both significantly increased the glucokinase mRNA level, while naringin also lowered the mRNA expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. In addition, the hepatic glucose transporter 2 protein expression was significantly reduced, while the expression of adipocyte glucose transporter 4 and hepatic and adipocyte peroxisome proliferator-activated receptor gamma were elevated in the hesperidin and naringin groups when compared with the control group. Furthermore, hesperidin and naringin effectively lowered the plasma free fatty acid and plasma and hepatic triglyceride levels, and simultaneously reduced the hepatic fatty acid oxidation and carnitine palmitoyl transferase activity. These changes were seemingly attributable to a suppression of the hepatic fatty acid synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase activities and an increase in the fecal triglycerides. The two flavonoids also led to a decrease in the plasma and hepatic cholesterol levels that may have been partly due to the decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase and acyl CoA: cholesterol acyltransferase (ACAT) activities and increased fecal cholesterol. Consequently, the current results suggest that hesperidin and naringin are beneficial for improving hyperlipidemia and hyperglycemia in type-2 diabetic animals by partly regulating the fatty acid and cholesterol metabolism and affecting the gene expression of glucose-regulating enzymes.
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PMID:Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. 1642 99

The NADP(H)-dependent enzymes glucose-6-phosphate dehydrogenase (G6PDH) and ferredoxin(flavodoxin)-NADP(H) reductase (FPR), encoded by the zwf and fpr genes, respectively, are committed members of the soxRS regulatory system involved in superoxide resistance in Escherichia coli. Exposure of E. coli cells to the superoxide propagator methyl viologen (MV) led to rapid accumulation of G6PDH, while FPR was induced after a lag period of several minutes. Bacteria expressing G6PDH from a multicopy plasmid accumulated higher NADPH levels and displayed a protracted soxRS response, whereas FPR build-up had the opposite effects. Inactivation of either of the two genes resulted in enhanced sensitivity to MV killing, while further increases in the cellular content of FPR led to higher survival rates under oxidative conditions. In contrast, G6PDH accumulation over wild-type levels of expression failed to increase MV tolerance. G6PDH and FPR could act concertedly to deliver reducing equivalents from carbohydrates, via NADP(+), to the FPR acceptors ferredoxin and/or flavodoxin. To evaluate whether this electron-transport system could mediate reductive repair reactions, the pathway was reconstituted in vitro from purified components; the reconstituted system was found to be functional in reactivation of oxidatively damaged iron-sulfur clusters of hydro-lyases such as aconitase and 6-phosphogluconate dehydratase. Recovery of these activities after oxidative challenge was faster and more extensive in transformed bacteria overexpressing FPR than in wild-type cells, indicating that the reductase could sustain hydro-lyase repair in vivo. However, FPR-deficient mutants were still able to fix iron-sulfur clusters at significant rates, suggesting that back-up routes for ferredoxin and/or flavodoxin reduction might be called into action to rescue inactivated enzymes when FPR is absent.
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PMID:Glucose-6-phosphate dehydrogenase and ferredoxin-NADP(H) reductase contribute to damage repair during the soxRS response of Escherichia coli. 1654 75

Chlorotic and green needles from Norway spruce (Picea abies L.) trees were sampled in the Calcareous Bavarian Alps in winter. The needles were used for analysis of the mineral and pigment contents, the levels of antioxidants (ascorbate, glutathione), and the activities of protective enzymes (superoxide dismutase, catalase, ascorbate peroxidase, monodehydroascorbate radical reductase, dehydroascorbate reductase, glutathione reductase). In addition, the activities of two respiratory enzymes (glucose-6-phosphate dehydrogenase, NAD-malate dehydrogenase), which might provide the NADPH necessary for functioning of the antioxidative system, were determined. We found that chlorotic needles were severely manganese deficient (3 to 6 micrograms Mn per gram dry weight as compared with up to 190 micrograms Mn per gram dry weight in green needles) but had a similar dry weight to fresh weight ratio, had a similar protein content, and showed no evidence for enhanced lipid peroxidation as compared with green needles. In chlorotic needles, the level of total ascorbate and the activities of superoxide dismutase, monodehydroascorbate radical reductase, NAD-malate dehydrogenase, and glucose-6-phosphate dehydrogenase were significantly increased, whereas the levels of ascorbate peroxidase, dehydroascorbate reductase, glutathione reductase, and glutathione were not affected. The ratio of ascorbate to dehydroascorbate was similar in both green and chlorotic needles. These results suggest that in spruce needles monodehydroascorbate radical reductase is the key enzyme involved in maintaining ascorbate in its reduced state. The reductant necessary for this process may have been supplied at the expense of photosynthate.
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PMID:Antioxidants and Manganese Deficiency in Needles of Norway Spruce (Picea abies L.) Trees. 1666 74

Biochemical responses to cadmium (Cd2+) and copper (Cu2+) exposure were compared in two strains of the aquatic hyphomycete (AQH) Heliscus lugdunensis. One strain (H4-2-4) had been isolated from a heavy metal polluted site, the other (H8-2-1) from a moderately polluted habitat. Conidia of the two strains differed in shape and size. Intracellular accumulation of Cd2+ and Cu2+ was lower in H4-2-4 than in H8-2-1. Both strains synthesized significantly more glutathione (GSH), cysteine (Cys) and gamma-glutamylcysteine (gamma-EC) in the presence of 25 and 50 microM Cd2+, but quantities and rates of synthesis were different. In H4-2-4, exposure to 50 microM Cd2+ increased GSH levels to 262% of the control; in H8-2-1 it increased to 156%. Mycelia of the two strains were analysed for peroxidase, dehydroascorbate reductase, glutathione reductase and glucose-6-phosphate dehydrogenase. With Cd2+ exposure, peroxidase activity increased in both strains. Cu2+ stress increased dehydroascorbate reductase activity in H4-2-4 but not in H8-2-1. Dehydroascorbate reductase and glucose-6-phosphate dehydrogenase activities progressively declined in the presence of Cd2+, indicating a correlation with Cd2+ accumulation in both strains. Cd2+ and Cu2+ exposure decreased glutathione reductase activity.
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PMID:Stress response in two strains of the aquatic hyphomycete Heliscus lugdunensis after exposure to cadmium and copper ions. 1690 Apr


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