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PubMed1995

Differential susceptibility of filarial and human erythrocyte glutathione reductase to inhibition by the trivalent organic arsenical melarsen oxide.

The glutathione reductases (GR) from two cattle filariae (Setaria digitata and Onchocerca gutturosa) have been isolated and their properties have been compared to those of human erythrocyte GR. In general, the enzymes appear to be very similar with respect to substrate-specificity for glutathione disulfide and NADPH, molecular mass (97 kDa vs. 98 kDa) and oligomeric organisation (subunit size of 51 kDa vs. 50 kDa). However, studies on the inhibition of the enzymes by the trivalent melaminophenyl arsenical melarsen oxide revealed that the human GR is less susceptible to inhibition by the arsenical than the filarial enzymes. Further, it was found that the mechanism of inactivation differs for the host and filarial enzymes. The human enzyme is inhibited by melarsen oxide in a competitive manner with a Ki of 23.7 microM, whereas the filarial GRs are inhibited in two stages: an immediate partial inactivation followed by a time-dependent stage with saturable pseudo-first-order kinetics. Ki values for the S. digitata and O. gutturosa GRs are 38.3 microM and 4.5 microM, respectively, with maximum second-stage inactivation rates of 1.0 x 10(-4) s-1 and 24.3 x 10(-4) s-1, respectively. These differences between host and parasite enzyme might reflect differences in the primary and secondary structure of the proteins which might be exploitable for the design of new specific macrofilaricidal drugs.

Animals↗
PubMed1999

Assessment of glutathione-S-transferase and glutathione reductase in patients with squamous-cell carcinoma of buccal mucosa.

Serum and tumor cytosolic levels of glutathione-S-transferase (GST) and glutathione-reductase (GR) activity were determined spectrophotometrically. The levels were correlated with clinicopathological criteria and a tobacco-associated protein band (T band) found in serum. The results showed significantly decreased mean serum GST levels (p < 0.02) in cancer patients as compared with controls. However, mean serum GR levels were significantly higher in patients than in controls (p < 0.01). T-band-positive patients showed low GST and low GR activity as compared with T-band-negative patients. Tumor cytosolic-enzyme levels of GST and GR activity were significantly higher (p < 0.0003 and p < 0.0001, respectively) than in corresponding adjacent noncancerous mucosa. Tumour cytosolic GST and GR activity showed significant association with clinicopathologic criteria, e.g., stage, histologic grade and nodal involvement. T-band-negative patients showed significantly higher levels of GST (p < 0.0001) than did T-band-positive patients. Low levels of cytosolic GST may be associated with increased susceptibility towards carcinogen-induced damage. The results suggest that the presence of T band in the sera may be associated with a high-risk phenotype due to decreased detoxification ability.

Adult↗
PubMed1982

ACP1GUA-1--a low-activity variant of human erythrocyte acid phosphatase: association with increased glutathione reductase activity.

ACP1GUA-1, a variant of human erythrocyte acid phosphatase, exists as a polymorphism (allele frequency of .132) in the Guaymi Indians of Central America. This variant has an electrophoretic mobility similar to the common B- and C-type variants, but individuals of the ACP1GUA-1 phenotype have a level of enzyme activity only 27% of the activity expected for the ACP1C variant. The GUA-1 variant is more thermostable than is the B variant, and the order of responsiveness to the modulation of activity by purine analogs and folate is always (B)-(A)-(GUA-1). Thus, the GUA-1 variant is a low-activity variant with C-like regulatory properties. Erythrocytes from individuals of the ACP1GUA-1 phenotype have increased basal levels of glutathione reductase, and a larger fraction of the glutathione reductase protein is present as the holoenzyme, indicating increased levels of flavin adenine dinucleotide in the erythrocytes of these individuals. This is consistent with the suggestion that ACP1 has a physiological function as a flavin mononucleotide phosphatase.

Acid Phosphatase↗
PubMedDate not supplied

[The effect of nicotinamide on the activity of the glutathione- glutathione reductase system in subcellular fractions of regenerating rat liver].

Experiments on white rats have shown that growth rates of the glutathione reductase activity and reduced glutathione concentration in the cytoplasmic fraction of the generating liver tissue and especially in the mitochondrial one are more pronounced with an increase of the nicotinamide dose from 50 mg/kg to 150 mg/kg, than after administration of nicotinamide in a dose of 300 mg/kg. Higher doses of nicotinamide (500 mg/kg) produce less pronounced changes in these parameters.

Animals↗
PubMed1990

Steady-state and laser flash induced photoreduction of yeast glutathione reductase by 5-deazariboflavin and by a viologen analogue: stabilization of flavin adenine dinucleotide semiquinone species by complexation.

Steady-state and laser flash photolysis techniques have been used to examine the photoreduction of yeast glutathione reductase by the one-electron reduction products of 5-deazariboflavin and the viologen analogue 1,1'-propylene-2,2'-bipyridyl. Steady-state photoreduction of the enzyme with the viologen generates the two-electron-reduced form, whereas photoreduction with deazaflavin generates the anion semiquinone. Flash photolysis indicates that the product of viologen radical reduction is also a semiquinone, suggesting that this species is rapidly further reduced by viologen in the steady-state experiment to form the EH2 enzyme. This reduction is apparently inhibited when deazaflavin is the photoreductant, perhaps due to complexation of the anion semiquinone with deazaflavin. Steady-state experiments demonstrate that complexation of the anion semiquinone with NADP+ also inhibits further reduction. Both one-electron reduction reactions of oxidized glutathione reductase proceed at close to diffusion-controlled rates (second-order rate constants = 10(8)-10(9) M-1 s-1), despite the relatively buried nature of the FAD cofactor. Addition of NADP+ and oxidized glutathione produced no effects on the kinetics of the initial entry of the electron into the enzyme. No kinetic evidence of intramolecular electron transfer involving the FAD and the protein disulfide was obtained during or subsequent to the initial one-electron reduction process. Thus, if this reaction occurs in the semiquinone, it must be quite rapid (k greater than 8000 s-1).

Chemical Phenomena↗
PubMed1995

Paraquat tolerance of transgenic Nicotiana tabacum with enhanced activities of glutathione reductase and superoxide dismutase.

Transgenic tobacco with enhanced cytosolic activities of glutathione reductase and superoxide dismutase were generated by cross-fertilization. Leaves of the hybrids exhibited further increased tolerance to a O2-.-generating herbicide paraquat than those of their parents. This result indicates the efficiency of manipulating more than one gene in improving resistance of plants to photooxidative stress.

Drug Resistance↗
PubMed1984

Purification and properties of glutathione reductase from the cyanobacterium Anabaena sp. strain 7119.

An NADPH-glutathione reductase (EC 1.6.4.2) has been purified 6,000-fold to electrophoretic homogeneity from the filamentous cyanobacterium Anabaena sp. strain 7119. The purified enzyme exhibits a specific activity of 249 U/mg and is characterized by being a dimeric flavin adenine dinucleotide-containing protein with a ratio of absorbance at 280 nm to absorbance at 462 nm of 5.8, a native molecular weight of 104,000, a Stokes radius of 4.13 nm, and a pI of 4.02. The enzyme activity is inhibited by sulfhydryl reagents and heavy-metal ions, especially in the presence of NADPH, with oxidized glutathione behaving as a protective agent. As is the case with the same enzyme from other sources, the kinetic data are consistent with a branched mechanism. Nevertheless, the cyanobacterial enzyme presents three distinctive features with respect to that isolated from non-photosynthetic organisms: (i) absolute specificity for NADPH, (ii) an alkaline optimum pH value of ca. 9.0, and (iii) strong acidic character of the protein, as estimated by column chromatofocusing. The kinetic parameters are very similar to those found for the chloroplast enzyme, but the molecular weight is lower, being comparable to that of non-photosynthetic microorganisms. A protective function, analogous to that assigned to the chloroplast enzyme, is suggested.

Amino Acids↗
PubMedDate not supplied

[Glucose-6-phosphate dehydrogenase, glutathione reductase, succinate dehydrogenase activities and content of sodium and potassium in kidneys of epiphysisectomized rats under spontaneous diuresis and water load].

The paper is concerned with the effect of epiphysisectomy on the glucose-6-phosphate dehydrogenase, glutathion reductase, succinate dehydrogenase activities and the content of sodium and potassium in the cortex and medullary layers of the kidneys under spontaneous diuresis and water load. It is shown that in rats without epiphysis the activity of glucose-6-phosphate dehydrogenase is lowered both in the cortex and medullary layers of the kidneys. The activity of glutathion reductase rises in the cortex layer of the kidneys only under water load. A disturbance is found in the sodium and potassium distribution between the cortex and medullary layers of the kidneys. An assumption is advanced on a possible role of epiphysis in regulating the kidney functions.

Animals↗
PubMed1990

Role of the charged groups of glutathione disulfide in the catalysis of glutathione reductase: crystallographic and kinetic studies with synthetic analogues.

Six analogues of glutathione disulfide were synthesized. All of them involved the abolishment of charges, either by amidation of carboxylates or by removal of amino groups. Four of these analogues could be bound to crystalline oxidized glutathione reductase, and their binding modes could be established by X-ray analyses at 2.4-A resolution. All six analogues were catalytically processed; the kinetic parameters were determined. The two analogues that did not bind in the crystals had by far the poorest catalytic efficiencies. Kinetic parameters together with X-ray data show the influence of each charged group on binding and catalytic rate. Data analysis indicates that the enzyme avoids processing of incorrect substrates in two ways: First, it reduces their binding strengths and/or enforces displacement of catalytically important substrate parts. Furthermore, it forms a fragile cluster of bound substrate and catalytically competent residues, which is unbalanced by incorrect parts of the substrate such that catalysis is prevented. A scouting microcalorimetric study using glutathione disulfide yielded a binding enthalpy of -103 (+/- 10) kJ/mol at 25 degrees C and a heat capacity change of -8 (+/- 1) kJ.mol-1.K-1. The study showed that it is feasible to measure these parameters as a function of substrate modification.

Catalysis↗
PubMed1992

Molecular characterization of glutathione reductase cDNAs from pea (Pisum sativum L.).

A cDNA for pea glutathione reductase has been cloned and sequenced. The derived amino acid sequence of 562 residues shows a high degree of homology to the previously published GR sequences from human erythrocytes and from two prokaryotes: Escherichia coli and Pseudomonas aeruginosa. The pea enzyme differs from other GRs in having an N-terminal leader sequence of about 60-70 residues which may be a chloroplast transit peptide and a 20 amino acid C-terminal extension of unknown function.

Amino Acid Sequence↗
PubMed1991

The three-dimensional structure of glutathione reductase from Escherichia coli at 3.0 A resolution.

The structure of glutathione reductase from Escherichia coli has been solved at 3 A resolution using multiple isomorphous replacement, solvent flattening, and molecular replacement on the basis of the homologous (53% identical residues) and structurally well-established human enzyme. The structures of both enzyme species agree with each other in a global way; there is no domain rearrangement. In detail, clear structural differences can be observed. The structure analysis of the E. coli enzyme was tackled in order to understand site-directed mutants, the most spectacular of which changed the cofactor specificity of this enzyme from NADP to NAD (Scrutton et al., 1990, Nature 343:38-43).

Escherichia coli↗
PubMed2000

Post-transcriptional regulation prevents accumulation of glutathione reductase protein and activity in the bundle sheath cells of maize.

Glutathione reductase (GR; EC 1.6.4.2) activity was assayed in bundle sheath and mesophyll cells of maize (Zea mays L. var H99) from plants grown at 20 degrees C, 18 degrees C, and 15 degrees C. The purity of each fraction was determined by measuring the associated activity of the compartment-specific marker enzymes, Rubisco and phosphoenolpyruvate carboxylase, respectively. GR activity and the abundance of GR protein and mRNA increased in plants grown at 15 degrees C and 18 degrees C compared with those grown at 20 degrees C. In all cases GR activity was found only in mesophyll fractions of the leaves, with no GR activity being detectable in bundle sheath extracts. Immunogold labeling with GR-specific antibodies showed that the GR protein was exclusively localized in the mesophyll cells of leaves at all growth temperatures, whereas GR transcripts (as determined by in situ hybridization techniques) were observed in both cell types. These results indicate that post-transcriptional regulation prevents GR accumulation in the bundle sheath cells of maize leaves. The resulting limitation on the capacity for regeneration of reduced glutathione in this compartment may contribute to the extreme chilling sensitivity of maize leaves.

Glutathione Reductase↗
PubMed1981

Mouse-liver glutathione reductase: inactivation by NADPH or two allelic variants.

Mouse-liver glutathione reductase has been purified to homogeneity from strain SWR/J by ammonium sulfate precipitation (40-80%) and two additional steps of affinity chromatography in ATPR-Sepharose and 2', 5'-ADP-Sepharose from which it was specifically eluted by using NADP+ gradients. After 2032-fold purification the pure enzyme has a specific activity of 146 U/mg. The SWR/J protein is slightly more basic than the other allelic variant from strain DBA/2J, with PI 7.0 and 6.5 respectively. Both pure proteins are immunologically identical, either by immunodiffusion or by quantitative immunoprecipitation, They can however be distinguished by their rate of inactivation in the presence of NADPH, their reduced cofactor. The SWR/J protein is much more resistant to that inactivation (t1/2 = 14 min) than the DBA/2J enzyme (t1/2 = 5 min).

Alleles↗
PubMed1998

Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue.

Plasmodium falciparum glutathione reductase (PfGR) has emerged as a drug target against tropical malaria. Here we report the expression of PfGR in Escherichia coli SG5(DE3) and isolation procedures for this protein. Recombinant PfGR does not differ from the authentic enzyme in its enzymic properties, the turnover number being 9900 min(-1). The dimeric flavoenzyme exhibits redox-dependent absorption spectra; the single tryptophan residue (per 57.2 kDa subunit) is strongly fluorescent. PfGR can be inhibited by the antimalarial drug methylene blue at therapeutic concentrations; the Ki for non-competitive inhibition is 6.4 microM. The sensitivity to methylene blue is observed also at high ionic strength so that, by analogy to human GR, analysis of crystalline enzyme-drug complexes can be envisaged.

Animals↗
PubMed1988

Glutathione reductase during and after brain ischemia in gerbils.

The activity of glutathione reductase (GR) was measured in crude mitochondrial fraction isolated from cerebral cortex and basal ganglia of Mongolian gerbils subjected to bilateral carotid occlusion of various duration (1, 2, 3, 5, 10, and 15 min), or reflow (1, 24, and 96 hr) following ischemia (5 or 15 min). Ischemia up to 5 min does not induce changes in GR activity in either structure. Basal ganglia activity is halved at 10 min and cortical at 15 min of ischemia. In reflow, basal ganglia GR activity is diminished, while cortical GR is transiently reduced at day 1 of reflow. The persistent and profound decrease in GR activity in basal ganglia following ischemia is indicative of the lowered antioxidative capacity of these cells, being possibly related to their greater vulnerability toward ischemia.

Animals↗
PubMed1998

Modulation of erythrocyte photohemolysis rate by glutathione reductase inactivating alkylating agents.

In order to determine the role of glutathione reductase (GR) in protection against Alphtalocyanine tetrasulfonate-sensitized human erythrocyte photolysis, we have studied the effects of antitumour alkylating agents that inactivate GR, on photohemolysis rate. The rates of inactivation of reduced GR decreased in order BCNU > pharanox (N-p-[bis-(2-chloroethyl)-amino]-phenylacetic acid N-oxide) > phenalol (N-p-[bis-(2-chloroethyl)-amino]-phenylacetyl-L- phenylalanine) > o-F- and p-F-lophenal (o- and p-isomers of N-p-[bis-(2-chloroethyl)-amino]-phenylacetyl-D,L-fluorophenylalanine) > D,L-melphalan. As supposed, erythrocyte photolysis was accelerated by BCNU and pharanox, however, it was slowed down by phenylalanine mustards. The latter effect was explained by singlet oxygen quenching and/or photooxidation reactions of these compounds. This points out to a possibility of certain phenylalanine derivatives to neutralize the side-effects of photodynamic therapy.

Alkylating Agents↗
PubMed1987

Glutathione reductase in human lens epithelium: FAD-induced in vitro activation.

Glutathione reductase (GR) activity was measured with and without the addition of flavin adenine dinucleotide (FAD) in freshly excised human lens epithelium following cataract surgery, and in control eye bank lens epithelium. Large individual variations in activity were found in both groups. Out of 32 epithelia obtained from cataractous lenses, 14 showed no measurable GR activity. Activity in eight of these 14 epithelia was restored after FAD was added, implying that the apo-enzyme in these 8 epithelia was functional but FAD was not available. Another group of 8 active epithelia showed a significant increase in GR activity upon the addition of FAD, suggesting a mixed population of active enzyme and available fraction of apo-enzyme which was reactivated by the addition of FAD. Unusually high GR activities were observed in epithelia of several patients. This correlated principally with daily intake of thyroxine which is known to have a direct effect on the metabolism of riboflavin. The fact that in a significant number of cataract patients epithelial GR was not active, and the observation that activity could be restored by adding in vitro FAD, demands that more attention should be given to riboflavin nutritional status and FAD synthesis in the eye.

Cataract↗