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PubMed1999

Prion protein-deficient neurons reveal lower glutathione reductase activity and increased susceptibility to hydrogen peroxide toxicity.

The prion protein (PrP) has a central role in the pathogenesis of transmissible spongiform encephalopathies (TSE). Accumulating evidence suggests that normal cellular PrP (PrP(c)) may be involved in copper homeostasis and modulation of copper/zinc superoxide dismutase (Cu/ZnSOD) activity in neurons. Hydrogen peroxide (H(2)O(2)) is a toxic reactive oxygen species generated through normal cellular respiration, and neurons contain two important peroxide detoxifying systems (glutathione pathway and catalase). To determine whether PrP expression affects neuronal resistance to H(2)O(2), we exposed primary cerebellar granule neuron cultures derived from PrP knockout (PrP(-/-)) and wild-type (WT) mice to H(2)O(2) for 3, 6, and 24 hours. The PrP(-/-) neurons were significantly more susceptible to H(2)O(2) toxicity than WT neurons after 6 and 24 hours' exposure. The increased H(2)O(2) toxicity may be related to a significant decrease in glutathione reductase activity measured in PrP(-/-) neurons both in vitro and in vivo. This was supported by the finding that inhibition of GR activity with 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) increased H(2)O(2) toxicity in WT neurons over the same exposure period. The PrP toxic peptide PrP106-126 significantly reduced neuronal glutathione reductase activity and increased susceptibility to H(2)O(2) toxicity in neuronal cultures suggesting that PrP toxicity in vivo may involve altered glutathione reductase activity. Our results suggest the pathophysiology of prion diseases may involve perturbed PrP(c) function with increased vulnerability to peroxidative stress.

Animals↗
PubMed1982

Phosphoribosyl pyrophosphate synthetase and glutathione reductase in erythrocytes from hyperuricaemic and gout patients.

The enzymic activities of erythrocyte phosphoribosyl pyrophosphate synthetase (EC 2.7.6.1) and glutathione reductase (EC 1.6.4.2) have been measured in 54 primary gout patients, 35 individuals having hyperuricaemia and 51 healthy controls. Statistical analyses have shown a significant increase (p less than 0.01) in the enzymic activity of erythrocyte PRPP synthetase in both the hyperuricaemic and gout groups compared with the controls. No correlation between activity and age was found in any of the three clinical groups. A significant decrease (p congruent to 0.01) was found in the enzymic activity of red cell glutathione reductase in the gout group compared with the other two groups. The biochemical significance of the changes in enzymic activities of the two enzymes in primary gout is discussed.

Erythrocytes↗
PubMed1981

Low red cell activity of pyridoxine (pyridoxamine) phosphate oxidase and glutathione reductase associated with thalassaemia.

It was demonstrated in heterozygous alpha 1- and beta-thalassaemia, that the slow rate of red-cell metabolism of vitamin B6, previously shown to be inherited, is regulated by the FMN-dependent pyridoxine (pyridoxamine) phosphate oxidase, as in control subjects. In this study, 60% of the patients with thalassaemia had a low B6 oxidase activity. An inverse correlation with the stimulation of the FAD-dependent glutathione reductase activity by FAD confirmed that red-cell riboflavin status was responsible. The inherited nature and lack of signs of nutritional riboflavin deficiency led to the conclusion that this was the result of a slow rate of red-cell metabolism of riboflavin. Stimulation of glutathione reductase activity by FAD correlated inversely with its basic activity in thalassaemia and control subjects. There was a high incidence of a low activity of this enzyme per red cell in patients with thalassaemia. The possibility that a low activity of glutathione reductase and a slow metabolism of B6 and riboflavin in the red-cell might play a part in the degree of severity of the thalassaemic disease is discussed.

Erythrocytes↗
PubMed1987

Flavin binding site differences between lipoamide dehydrogenase and glutathione reductase as revealed by static and time-resolved flavin fluorescence.

Subnanosecond-resolved fluorescence measurements of the FAD bound in glutathione reductase and lipoamide dehydrogenase revealed characteristic differences in dynamic properties of both enzymes, which are considered to have common structural features. The flavin fluorescence in glutathione reductase is quenched mainly via a dynamic mechanism, in agreement with enhanced flexibility of the flavin as inferred from rapid depolarization of the fluorescence.

Allosteric Site↗
PubMed1989

Nitrofuran inhibition of yeast and rat tissue glutathione reductases. Structure-activity relationships.

Nitrofuran derivatives bearing unsaturated five- or six-membered nitrogen heterocycles or related substituents were more effective inhibitors of yeast and rat tissue glutathione reductases than those bearing other groups, such as nifurtimox, nitrofurazone and 5-nitro-2-furoic acid. The inhibitory action proved independent of electron withdrawal from the reduced enzyme, as a consequence of redoxcycling of the nitro group. Uncompetitive kinetics was obtained with nitrofurantoin and nifurtimox. Most of the assayed nitrofurans inhibited the yeast enzyme Coenzyme A glutathione disulfide reductase activity, though less than oxidized glutathione reduction. The transhydrogenase activity was not inhibited to a significant degree. Benznidazole (a 2-nitroimidazole derivative), 2-nitroimidazole, 5-nitroindole and chloramphenicol did not inhibit glutathione reductase. Under the same experimental conditions, liver glutathione peroxidase was not affected by the nitro compounds.

Animals↗
PubMed1981

A biochemical evaluation of the erythrocyte glutathione reductase (EC 1.6.4.2) test for riboflavin status. 2. Dose-response relationships in chronic marginal deficiency.

1. Chronic marginal riboflavin deficiency was induced in groups of weanling rats by feeding a deficient diet supplemented with 0, 0.5, 1.0 and 1.5 mg riboflavin/kg diet. Ad lib.- and pair-fed controls received 3.0 and 15 mg riboflavin/kg diet respectively. 2. Serial measurement of erythrocyte NAD(P)H2 glutathione oxidoreductase (glutathione reductase; EC 1.6.4.2) and its activation coefficient revealed that after 12 weeks a steady-state of deficiency had been reached following initial fluctuations in status; the animals were then killed, and their tissues analysed. 3. Food intake, growth rate and the appearance of pathological signs were directly proportional to riboflavin content; however relative liver weight was increased above control levels only in the most-severely-deficient group, and anaemia was not detected in any group. 4. The activation coefficient of glutathione reductase in erythrocytes and liver was closely related to dietary riboflavin content; that of skin responded maximally even in the least-severely-depleted animals. 5. Hepatic and renal flavin contents were directly proportional to dietary riboflavin, FAD being conserved at the expense of riboflavin and FMN. ATP:riboflavin 5-phosphotransferase (flavokinase; EC 2.7.1.26) activity was reduced, even in the least-severely-deficient animals; ATP:FMN adenylyltransferase(FAD pyrophosphorylase; EC 2.7.7.2) was increased in liver, but only in the most-severely-deficient animals. 6. Hepatic succinate:(acceptor) oxidoreductase (succinate dehydrogenase; EC 1.3.99.1) activity fell sharply between 1.5 and 0.5 mg riboflavin/kg diet, producing an S-shaped dose-response curve; it showed smaller or less specific changes in other tissues such as brain, skin and intestine. NADH:(acceptor) oxidoreductase (NADH dehydrogenase; EC 1.6.99.3) activity declined in liver and intestine, but not in skin or brain. 7. The activation coefficient of glutathione reductase was correlated strongly with nearly all the riboflavin-sensitive variables measured, once equilibrium had been reached in this chronic deficiency model, and it was particularly strongly correlated with hepatic and renal FAD levels. Under equilibrium conditions, therefore, it appears to represent a good index of the extent of riboflavin deficiency, and significant changes in flavin levels and enzymes in the internal organs were detected even under conditions of marginal deficiency, associated with relatively small increases in the activation coefficient.

Animals↗
PubMedDate not supplied

[Effect of UV-radiation on the level of ascorbic acid, SH-groups, and activity of glutathione reductase in the eye lens].

The effect of UV radiation in vitro on the level of ascorbate, SH-groups and glutathione reductase activity in the soluble fraction of bovine eye lens was studied. UV-Irradiation increased NADPH-oxidoreductase activity, the level of ascorbate oxidation and decreased the content of SH-groups and activity of glutathione reductase. Significant activation of the NADPH-oxidoreductase activity in the presence of ascorbate and Cu2+ was observed after UV-irradiation. It is suggested that ascorbate may play an important role in the UV-induced lens pathology.

Animals↗
PubMed1995

Glutathione reductase (EC 1.6.4.2.) in experimental trypanosomiasis.

The activity of glutathione reductase (GHSR) in extracts of kidney, liver and testis of rats infected with Trypanosoma congolense decreased with every wave of parasitemia. The implications of these observations as they relate to the risk of oxidative stress are discussed.

Animals↗
PubMed1978

Refined mapping of the gene for glutathione reductase on human chromosome 8.

Activity of the enzyme glutathione reductase (EC 1.6.4.2) in erythrocytes and fibroblasts of a patient with karyotype 46, XY, del(8) (pter-p212:) was found to be in the normal range. With results from other laboratories, this allowed a more precise mapping of the gene for this enzyme in the region 8p2100-8p212.

Child↗
PubMed2005

Purification of glutathione reductase from chicken liver and investigation of kinetic properties.

Glutathione reductase was purified from chicken liver and some characteristics of the enzyme were investigated. The purification procedure was composed of four steps: preparation of homogenate, ammonium sulfate precipitation, 2',5'-ADP Sepharose 4B affinity chromatography, and Sephadex G-200 gel filtration chromatography. Owing to the four consecutive procedures, the enzyme was purified 1714-fold, with a yield of 38%. Specific activity at the final step was 120 enzyme unit (EU)/mg of protein. The purified enzyme showed a single band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The molecular weight of the enzyme was found to be 100 kDa by Sephadex G-200 gel filtration chromatography, and the subunit molecular weight was found to be 43 kDa by SDS-PAGE. Optimum pH, stable pH, optimum ionic strength, and optimum temperature were 7.0, 7.4, 0.75 M Tris-HCl buffer including 1 mM EDTA, and 50 degrees C, respectively. KM and Vmax values for NADPH and glutathione disulfide (GSSG) substrates were also determined for the enzyme.

Ammonium Sulfate↗
PubMed1990

The red blood cell glutathione reductase activity in anaemic rats.

The enzyme activity of glutathione reductase (GR, EC 1.6.4.2) was measured in rat red blood cells separated centrifugally in a density gradient of Percoll. The animals were divided into three groups: Groups IPHH, anaemia was induced by administration of phenylhydrazine hydrochloride; Group IITr, anaemia was induced by intense physical training; and Group C, control group. The activity of active and inactive forms of GR were higher in erythrocytes of animals from groups IPHH and IITr, both in young and old forms of cells, than in red cells of control rats, the degree of decrease in activity of both forms of GR in senescent red cells is similar in different kinds of anaemia.

Aging↗
PubMed1984

The effect of experimental anaemia on red cell glutathione reductase.

The effect of experimental anaemia on red cell glutathione reductase (GR) was investigated in rabbits, guinea-pigs and cattle. The ratio of active and inactive forms of GR did not change during the experimental period in either the rabbits or the cattle. However, there was a marked rise in the ratio of inactive form in the guinea-pigs during anaemia. It appears that, in addition to the most important regulator of GR activity, namely the flavin content of the red blood cells, there are other mechanisms which are operating in the red blood cells of anaemic animals and that these mechanisms vary among different species of animals.

Anemia↗
PubMed1991

Structural, spectroscopic and catalytic activity studies on glutathione reductase reconstituted with FAD analogues.

FAD-modified human glutathione reductases were reconstituted from apoenzyme using the FAD analogues 6-SH-FAD, 6-SCN-FAD, 6-OH-FAD, 6-NH2-FAD and 8-OH-FAD. The catalytic activities of the modified enzymes were substantially lower than for the native enzyme. All five species could be crystallized, but only those containing 6-SH-FAD, 6-OH-FAD and 6-NH2-FAD yielded crystals that could be analyzed. X-ray analyses and structural refinements were performed at 0.27 nm and 0.30 nm resolution resulting in R factors around 13.5%. The crystal structures showed the additional non-hydrogen atoms and small conformational changes of the polypeptide that were obviously induced by the substituents of the FAD analogues. The observed changes together with spectroscopic and activity data permit some conclusions about the chemical nature of the substituents.

Catalysis↗
PubMed1997

Thermal denaturation of glutathione reductase from cyanobacterium Spirulina maxima.

The thermal unfolding of glutathione reductase (NAD[P]H:GSSG oxidoreductase EC 1.6.4.2.) from cyanobacterium Spirulina maxima was monitored by differential scanning calorimetry and circular dichroism at neutral pH. Covalent cross-linking of enzyme at different temperatures revealed dimer as the species undergoing the thermal transition. A single endotherm was observed, but its thermodynamic parameters showed dependence on the scan rate. In the transition zone, aggregation of the dimeric species was observed. Analysis of the enzyme heated at 80 degrees C revealed that the resultant species retained a high content of secondary structure. The addition of low concentrations of guanidinium hydrochloride resulted in a full cooperative thermal transition. A model in which the dimeric protein undergoes a partial unfolding in a kinetically controlled fashion is proposed, such that the experimental value of delta H(cal) results from the simultaneous occurrence of endothermic and exothermic events.

Bacterial Proteins↗
PubMed2003

Characterization of the targeting signal of dual-targeted pea glutathione reductase.

We investigated the dual targeting signal of pea glutathione reductase (GR) that had been previously shown to be capable of targeting the passenger protein phosphinothricin acetyl transferase to mitochondria and chloroplasts in vivo. We confirmed that GR was imported into mitochondria and chloroplasts in vitro. Rupture of the outer mitochondrial membrane after the import assay indicated that GR was imported into both the intermembrane space and the matrix. Changing positive and hydrophobic residues in the targeting signal we investigated if dual targeting of GR was due to an overlapping or separate signal. Overall single mutations had a greater effect on mitochondrial import compared to chloroplasts, especially those on positive residues. Precursors containing both positive and hydrophobic residue mutations (double mutants) indicated that there might be some redundancy in targeting information for chloroplastic import as double mutants had a greater effect than predicted from the single mutants. Fusion of the targeting signal to the green fluorescent protein (GFP) followed by transient transformation indicated that this signal was only capable of targeting this passenger protein to plastids. Additionally, fusion of the complete coding sequence of GR to GFP also resulted in an exclusive chloroplastic localization. Mutations in the targeting signal that reduced import into plastids in vitro also displayed altered patterns of GFP localizations in vivo. These results indicate that some residues in the signal for dual localisation of GR play a role in both mitochondrial and chloroplastic import, and thus the signal is overlapping.

Amino Acid Sequence↗
PubMed2004

Evidence for a novel mechanism of time-resolved flavin fluorescence depolarization in glutathione reductase.

Time-resolved flavin fluorescence anisotropy studies on glutathione reductase (GR) have revealed a remarkable new phenomenon: wild-type GR displays a rapid process of fluorescence depolarization, that is absent in mutant enzymes lacking a nearby tyrosine residue that blocks the NADPH-binding cleft. Fluorescence lifetime data, however, have shown a more rigid active-site structure for wild-type GR than for the tyrosine mutants. These results suggest that the rapid depolarization in wild-type GR originates from an interaction with the flavin-shielding tyrosine, and not from restricted reorientational motion of the flavin. A novel mechanism of fluorescence depolarization is proposed that involves a transient charge-transfer complex between the tyrosine and the light-excited flavin, with a concomitant change in the direction of the emission dipole moment of the flavin. This interaction is likely to result from side-chain relaxation of the tyrosine in the minor fraction of enzyme molecules in which this residue is in an unsuitable position for immediate fluorescence quenching at the moment of excitation. Support for this mechanism is provided by binding studies with NADP+ and 2'P-5'ADP-ribose that can intercalate between the flavin and tyrosine and/or block the latter. Fluorescence depolarization analyses as a function of temperature and viscosity confirm the dynamic nature of the process. A comparison with fluorescence depolarization effects in a related flavoenzyme indicates that this mechanism of flavin fluorescence depolarization is more generally applicable.

Algorithms↗
PubMed1994

The effects of age on glutathione peroxidase and glutathione reductase activities in lenses of Old World simians and prosimians.

The effects of age on the activities of the two enzymes of the glutathione redox cycle, glutathione peroxidase and glutathione reductase, were studied in lenses of primates. Three species were Old World simians (orangutan, olive baboon and pigtail monkey) and two were prosimians (galago and mouse lemur). Glutathione peroxidase activity of the olive baboon lens increased steadily with age while that of the pigtail monkey increased during the first 6-8 years and then plateaued. Enzyme activity in the orangutan increased steadily from 9 months to 28 years. This enzyme activity decreased steadily in the galago but increased only slightly in the mouse lemur lens. The lenticular glutathione reductase activity profiles showed decreases with age for all three simian species. Enzyme activity in the galago decreased gradually from birth to the age of 16.5 years. The enzyme activity values of the mouse lemur lens did not yield a comprehensible pattern. Lens weight increased with age in all five primate species, particularly in the infant and juvenile years and leveled off in adulthood. The current investigation demonstrated that the responses of these enzyme activities to aging were very different in Old World simians as compared to prosimians. These studies are consistent with earlier enzyme activity and thermolability data and are indicative of probable critical differences in the primary structures of the enzymes between the two primate groups.

Aging↗