Disease relevance of GSR

• The glutathione oxidant defence system in leucocytes and erythrocytes of six Anaplasma marginale-infected calves was examined by assaying glutathione peroxidase (GSH-px), glutathione reductase (GSSG-R), reduced glutathione (GSH) and superoxide dismutase (SOD) [1].
• This relaxation was enhanced by an inhibitor of glutathione reductase, and it was not altered by severe hypoxia, the presence of inhibitors of soluble guanylate cyclase, K(+) channels, tyrosine kinases, or probes that modulate levels of superoxide [2].

High impact information on GSR

• In the oxidized enzyme, we demonstrated two nonflavin redox centers by chemical modification and peptide sequencing: one was a disulfide within the sequence -Cys(59)-Val-Asn-Val-Gly-Cys(64), identical to the active site of GR; the other was a selenenylsulfide formed from Cys(497)-SeCys(498) and confirmed by mass spectrometry [3].
• Mammalian thioredoxin reductases (TrxR) are homodimers, homologous to glutathione reductase (GR), with an essential selenocysteine (SeCys) residue in an extension containing the conserved C-terminal sequence -Gly-Cys-SeCys-Gly [3].
• These findings suggest specifically N-nitrosation of glutathione reductase as a likely mechanism of inhibition elicited by dinitrosyl-iron complex and demonstrate in general that structural resemblance of an NO carrier with a natural ligand enhances NO+ transfer to the ligand-binding protein [4].
• Preincubation of cells with the glutathione reductase inhibitor, carmustine, led to elevated basal [Ca2+]i, yet the cells remained responsive to bradykinin [5].
• The effects of oxidant stress and inhibition of glutathione reductase on the bradykinin-stimulated changes in cytosolic free Ca2+ concentration ([Ca2+]i) of calf pulmonary artery endothelial cells were determined using the intracellular fluorescent probe, fura-2 [5].

Biological context of GSR

• The reductive half-reaction of TrxR is similar to that of GR followed by exchange from the nascent Cys(59) and Cys(64) dithiol to the selenenylsulfide of the other subunit to generate the active-site selenolthiol [3].
• These results suggest that inhibition of glutathione reductase alters cytosolic Ca2+ homeostasis and enhances the effects of oxidative stress on signal transduction in vascular endothelial cells [5].
• Glycation (non-enzymic glycosylation) inactivates glutathione reductase [6].
• Furthermore, inhibition of the mitochondrial respiratory chain (rotenone, antimycin A) or microsomal cytochrome P-450 (8-methoxypsoralen) did not change extracellular H2O2 release or intracellular H2O2 production (at peroxisomes) by endothelial cells or cells in which glutathione reductase was inactivated [7].
• LY83583 is reduced by NADPH and glutathione reductase in aerobic media and this may offer a route to the metabolic activation of LY83583 [8].

Anatomical context of GSR

• LY83583 (6-anilino-5,8-quinolinedione), considered to be a relatively specific repressor of cyclic GMP formation, is shown in the present study to inhibit (K(i) = 3 microM) glutathione reductase from bovine intestinal mucosa [8].
• Perfusion of the bovine eye with a buffer solution containing t-butyl hydroperoxide and the glutathione reductase inhibitor nitrofurantoin caused significant decreases in reduced glutathione level in ciliary body and iris [9].
• Treatment of the mitochondria with 1,3-bis(2-dichloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase, significantly decreased GSH level without producing discernible change in Ca2+ release and NAD(P)H oxidation [10].
• Hydrogen peroxide production, catalase and glutathione reductase activities by neutrophils incubated in presence of P. zopfii were stimulated five times, 21% and 27% respectively, compared to the unstimulated-neutrophils [11].

Associations of GSR with chemical compounds

• Glucose, glucose 6-phosphate and fructose all displayed a time-dependent inhibition of glutathione reductase activity, suggesting that these sugars glycate this enzyme [6].
• Inhibition of catalase, glutathione reductase, or gamma-glutamylcysteine synthetase did not change the rate of extracellular release of H2O2 [7].
• This study reports a new property of the important NAD(P)H-dependent flavoenzymes, glutathione reductase, lipoyl dehydrogenase and ferredoxin-NADP+ oxidoreductase, that can catalyze a one electron reduction of metal ions such as chromium(VI) and vanadium(V) [12].
• Reduction of a trisulfide derivative of glutathione by glutathione reductase [13].
• ESR measurements demonstrated that deferoxamine can efficiently reduce the concentration of the Cr(V) intermediate as formed in the reduction of Cr(VI) by NAD(P)H or a flavoenzyme glutathione reductase/NADH [14].

Other interactions of GSR

• BAECs overexpressing G6PD maintained intracellular glutathione stores when exposed to oxidants because of increased activity of glutathione reductase, an effect that was not observed in endothelial cells with normal G6PD activity [15].
• Neither drug inhibited glutathione reductase or superoxide dismutase at the concentrations tested; however, both inhibited catalase in a semilogarithmic fashion [16].
• The activities of antioxidant enzymes were almost unchanged (superoxide dismutase), decreased by 13% or 53% (catalase) or increased by 25% or 90% (glutathione reductase) in Mi-18 or FLK cells, respectively [17].
• Purification studies isolated two forms of glutathione reductase [GR I (140 kDa) with subunit Mr of 70 kDa and GR II (greater than 670 kDa) with subunit Mr of 45 kDa] and a novel glutathione peroxidase (112 kDa with subunit Mr of 29 kDa) [9].
• Finally, disruption of the glutathione redox cycle with the glutathione reductase inhibitor, 1,3-bis(2-chloroethyl)-1-nitrosourea, increased the extent of NO-mediated GAPDH inhibition and decreased both the rate and degree of recovery of GAPDH-activity [18].

Analytical, diagnostic and therapeutic context of GSR

• Susceptibility of glutathione peroxidase and glutathione reductase to oxidative damage and the protective effect of spin trapping agents [19].

References