Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The modifying effects of Crocus sativus (CS) stigma extract on neurobehavioral activities, malondialdehyde (MDA), reduced glutathione (GSH), glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase (SOD), catalase (CAT), and Na(+),K(+)-ATPase activities, and glutamate (Glu) and aspartate (Asp) content were examined in the middle cerebral artery (MCA) occlusion (MCAO) model of acute cerebral ischemia in rats. The right MCA of male Wistar rats was occluded for 2 hours using intraluminal 4-0 monofilament, and reperfusion was allowed for 22 hours. MCAO caused significant depletion in the contents of GSH and its dependent enzymes while significant elevation of MDA, Glu, and Asp. The activities of Na(+),K(+)-ATPase, SOD, and CAT were decreased significantly by MCAO. The neurobehavioral activities (grip strength, spontaneous motor activity, and motor coordination) were also decreased significantly in the MCAO group. All the alterations induced by ischemia were significantly attenuated by pretreatment of CS (100 mg/kg of body weight, p.o.) 7 days before the induction of MCAO and correlated well with histopathology by decreasing the neuronal cell death following MCAO and reperfusion. The present results may suggest the effectiveness of CS in focal ischemia most probably by virtue of its antioxidant property.
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PMID:Effect of Saffron (Crocus sativus) on neurobehavioral and neurochemical changes in cerebral ischemia in rats. 1682 11

In Anopheles dirus glutathione transferase D3-3, position 64 is occupied by a functionally conserved glutamate residue, which interacts directly with the gamma-glutamate moiety of GSH (glutathione) as part of an electron-sharing network present in all soluble GSTs (glutathione transferases). Primary sequence alignment of all GST classes suggests that Glu64 is one of a few residues that is functionally conserved in the GST superfamily. Available crystal structures as well as consideration of the property of the equivalent residue at position 64, acidic or polar, suggest that the GST electron-sharing motif can be divided into two types. Electrostatic interaction between the GSH glutamyl and carboxylic Glu64, as well as with Arg66 and Asp100, was observed to extend the electron-sharing motif identified previously. Glu64 contributes to the catalytic function of this motif and the 'base-assisted deprotonation' that are essential for GSH ionization during catalysis. Moreover, this residue also appears to affect multiple steps in the enzyme catalytic strategy, including binding of GSH, nucleophilic attack by thiolate at the electrophilic centre and product formation, probably through active-site packing effects. Replacement with non-functionally-conserved amino acids alters initial packing or folding by favouring aggregation during heterologous expression. Thermodynamic and reactivation in vitro analysis indicated that Glu64 also contributes to the initial folding pathway and overall structural stability. Therefore Glu64 also appears to impact upon catalysis through roles in both initial folding and structural maintenance.
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PMID:Glutamate-64, a newly identified residue of the functionally conserved electron-sharing network contributes to catalysis and structural integrity of glutathione transferases. 1710 Jun 54

Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders including primary open-angle glaucoma (POAG) an optic neuropathy characterized by loss of retinal ganglion cell (RGC) axons and remodeling of the optic nerve head (ONH). Previous findings in glaucomatous astrocytes suggested increased oxidative stress and lipid peroxidation in human optic nerves. We studied the dose and time dependent effects of 4-hydroxynonenal (HNE), a by-product of lipid peroxidation, on the viability of primary cultures of human ONH astrocyte. A significant depletion of glutathione (GSH) level was observed in normal astrocytes after exposure to HNE for 1 h and 3 h. Untreated glaucomatous astrocytes exhibited depleted levels of GSH which increased slightly after exposure to HNE. Both normal and glaucomatous astrocytes recovered GSH levels after 24 h of removal of HNE. HNE caused significant increases in expression of antioxidant enzymes, glutamate cysteine ligase catalytic subunit (GCLC), aldo-keto reductase 1C family member 1 (AKR1C1) and glutathione S-transferase-alpha4 (GSTA4). HNE induced expression of the transcription factor Nrf2, which coordinates the upregulation of detoxification enzymes. In addition, ONH astrocytes responded to HNE by activation and transcription of cFOS and NFkB, which regulate physiological protective responses against oxidative stress. Our results indicate that ONH astrocytes exhibit a strong antioxidant response to HNE treatment by inducing the transcription factors cFOS, NFkB, and Nrf2, which upregulate the expression of GCLC, to produce more GSH in the cell. AKR1C1 was also upregulated after HNE treatment to inactivate HNE, independent of GSH availability in the cells. Collectively these data indicate that ONH astrocytes can efficiently counteract the neurotoxic effects of HNE offering protection in the optic nerve by releasing GSH and antioxidant enzymes to eliminate the products of chronic oxidative stress.
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PMID:4-Hydroxynonenal, a product of oxidative stress, leads to an antioxidant response in optic nerve head astrocytes. 1717 95

The objective of the present study was to investigate the effects of aqueous garlic extract (AGE) on neurobehavioral activities, malondialdehyde (MDA) and reduced glutathione (GSH) levels, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and sodium-potassium ATPase (Na(+),K(+)-ATPase) activities, and glutamate and aspartate content in a middle cerebral artery (MCA) occlusion (MCAO) model of acute cerebral ischemia in rats. The right MCA of male Wistar rats was occluded for 2 hours using intraluminal 4-0 monofilament, and reperfusion was allowed for 22 hours. MCAO caused significant depletion in GSH and its dependent enzymes (GPx, GR, and GST) and significant elevation of MDA, glutamate, and aspartate. The activities of Na(+),K(+)- ATPase, SOD, and CAT were decreased significantly by MCAO. The neurobehavioral activities (grip strength, spontaneous motor activity, and motor coordination) were also decreased significantly in the MCAO group. All of the alterations induced by ischemia were significantly attenuated by pretreatment with AGE (500 mg/mL/kg of body weight, i.p.) 30 minutes before the induction of MCAO and correlated well with histopathology by decreasing the neuronal cell death following MCAO and reperfusion. These findings suggest that AGE effectively modulates neurobehavioral and neurochemical changes in focal ischemia, most probably by virtue of its antioxidant properties.
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PMID:Behavioral and histologic neuroprotection of aqueous garlic extract after reversible focal cerebral ischemia. 1720 42

Mice fed diets containing 3% or 6% coffee for 5 days had increased levels of mRNA for NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase class Alpha 1 (GSTA1) of between 4- and 20-fold in the liver and small intestine. Mice fed 6% coffee also had increased amounts of mRNA for UDP-glucuronosyl transferase 1A6 (UGT1A6) and the glutamate cysteine ligase catalytic (GCLC) subunit of between 3- and 10-fold in the small intestine. Up-regulation of these mRNAs was significantly greater in mice possessing Nrf2 (NF-E2 p45 subunit-related factor 2) than those lacking the transcription factor. Basal levels of mRNAs for NQO1, GSTA1, UGT1A6 and GCLC were lower in tissues from nrf2(-/-) mice than from nrf2(+/+) mice, but modest induction occurred in the mutant animals. Treatment of mouse embryonic fibroblasts (MEFs) from nrf2(+/+) mice with either coffee or the coffee-specific diterpenes cafestol and kahweol (C+K) increased NQO1 mRNA up to 9-fold. MEFs from nrf2(-/-) mice expressed less NQO1 mRNA than did wild-type MEFs, but NQO1 was induced modestly by coffee or C+K in the mutant fibroblasts. Transfection of MEFs with nqo1-luciferase reporter constructs showed that induction by C+K was mediated primarily by Nrf2 and required the presence of an antioxidant response element in the 5'-upstream region of the gene. Luciferase reporter activity did not increase following treatment of MEFs with 100 mumol/l furan, suggesting that this ring structure within C+K is insufficient for gene induction. Priming of nrf2(+/+) MEFs, but not nrf2(-/-) MEFs, with C+K conferred 2-fold resistance towards acrolein.
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PMID:Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein. 1802 74

Frequent consumption of green tea, one of the most popular and widely consumed beverages, has been known to protect against development of various cancers according to numerous experimental and several population-based studies. Molecular mechanisms underlying chemopreventive effects exerted by green tea and its components have been extensively investigated. (-)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, has been shown to induce expression of glutathione S-transferase, glutathione peroxidase, glutamate cysteine ligase, hemeoxygenase-1, etc. that are involved in the elimination or inactivation of reactive oxygen species and electrophiles implicated in multi-stage carcinogenesis. The redox-sensitive transcription factor, nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2) plays a key role in regulating induction of phase II detoxifying or antioxidant enzymes. Thus, activation of Nrf2 is considered to be an important molecular target of many chemopreventive and chemoprotective agents. This review summarizes the molecular basis of chemoprevention and cytoprotection afforded by EGCG with emphasis on its ability to modulate Nrf2-mediated cellular events.
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PMID:Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. 1808 23

Methanolic extract of Phyllanthus-polyphyllus was evaluated for hepatoprotective and antioxidant activities in rats. The plant extract (200 and 300 mg/kg, p.o.) showed a remarkable hepatoprotective and antioxidant activity against acetaminophen induced hepatotoxicity as judged from the serum marker enzymes and antioxidant levels in liver tissues. Acetaminophen induced a significant rise in aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin, gamma glutamate transpeptidase (GGTP), lipid peroxidase (LPO) with a reduction of total protein, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione S-transferase (GST). Treatment of rats with different doses of plant extract (200 and 300 mg/kg) significantly (P<0.001) altered serum marker enzymes and antioxidant levels to near normal against acetaminophen treated rats. The activity of the extract at dose of 300 mg/kg was comparable to the standard drug, silymarin (50 mg/kg, p.o.). Histopathological changes of liver sample were compared with respective control. Results indicate the hepatoprotective and antioxidant properties of Phyllanthus polyphyllus against acetaminophen-induced hepatotoxicity in rats.
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PMID:Protective effect of Phyllanthus polyphyllus on acetaminophen induced hepatotoxicity in rats. 1816 21

Recent studies have identified a novel family of oxidized phosphatidylcholines (oxPC(CD36)) that serve as highly specific ligands for scavenger receptor CD36. oxPC(CD36) accumulate in vivo and mediate macrophage foam cell formation as well as promote platelet hyper-reactivity in hyperlipidemia via CD36. The structural basis of oxPC(CD36) binding to CD36 has not been elucidated. We used liquid-phase binding to glutathione S-transferase fusion proteins containing various regions of CD36 to initially identify the region spanning CD36 amino acids 157-171 to contain a major binding site for oxPC(CD36). A bell-shaped pH profile and salt concentration dependence suggest an electrostatic mechanism of the binding. Two conserved, positively charged amino acids in the region 157-171 (lysines at positions 164 and 166) were identified as critical for oxPC(CD36) and oxidized low density lipoprotein (oxLDL) binding to CD36. Lysine neutralization with chemical modifier or site-directed mutagenesis of lysine 164/166 to alanine or glutamate, but not to arginine, abolished binding. Cells expressing full-length CD36 with mutated lysines (164 and 166) failed to recognize oxPC(CD36) and oxLDL. Synthetic peptides mimicking the CD36 binding site, but not mutated or scrambled peptides, effectively prevented: (i) oxLDL binding to CD36, (ii) macrophage foam cell formation induced by oxLDL, and (iii) platelet activation by oxPC(CD36). These data indicate that CD36 (160-168) represents the core of the oxPC(CD36) binding site with lysines 164/166 being indispensable for the binding.
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PMID:Mapping and characterization of the binding site for specific oxidized phospholipids and oxidized low density lipoprotein of scavenger receptor CD36. 1824 80

Glutathione (GSH) is an important antioxidant and cofactor for glutathione S-transferase conjugation. GSH synthesis is catalyzed by glutamate cysteine ligase (GCL), composed of catalytic (GCLC) and modifier (GCLM) subunits. Transgenic mice that conditionally over express GCL subunits are protected from acetaminophen induced liver injury. Gclm null mice exhibit low GSH levels and enhanced sensitivity to acetaminophen. When Gclm expression and GCL activity are restored in Gclm conditional transgenic X Gclm null mice, they become resistant to APAP-induced liver damage. These animal models are a valuable resource for investigating the role of GSH synthesis in modulating oxidative damage and drug-induced hepatotoxicity.
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PMID:Modulating GSH synthesis using glutamate cysteine ligase transgenic and gene-targeted mice. 1864 43

Metabotropic glutamate subtype-5 receptors (mGluR5) are implicated in several neuropsychiatric disorders. Positron emission tomography (PET) with a suitable radioligand may enable monitoring of regional brain mGluR5 density before and during treatments. We have developed a new radioligand, 3-fluoro-5-(2-(2-[(18)F](fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile ([(18)F]SP203), for imaging brain mGluR5 in monkey and human. In monkey, radioactivity was observed in bone, showing release of [(18)F]-fluoride ion from [(18)F]SP203. This defluorination was not inhibited by disulfiram, a potent inhibitor of CYP2E1. PET confirmed bone uptake of radioactivity and therefore defluorination of [(18)F]SP203 in rats. To understand the biochemical basis for defluorination, we administered [(18)F]SP203 plus SP203 in rats for ex vivo analysis of metabolites. Radio-high-performance liquid chromatography detected [(18)F]fluoride ion as a major radiometabolite in both brain extract and urine. Incubation of [(18)F]SP203 with brain homogenate also generated this radiometabolite, whereas no metabolism was detected in whole blood in vitro. Liquid chromatography-mass spectrometry analysis of the brain extract detected m/z 548 and 404 ions, assignable to the [M + H](+) of S-glutathione (SP203Glu) and N-acetyl-S-l-cysteine (SP203Nac) conjugates of SP203, respectively. In urine, only the [M + H](+) of SP203Nac was detected. Mass spectrometry/mass spectrometry and multi-stage mass spectrometry analyses of each metabolite yielded product ions consistent with its proposed structure, including the former fluoromethyl group as the site of conjugation. Metabolite structures were confirmed by similar analyses of SP203Glu and SP203Nac, prepared by glutathione S-transferase reaction and chemical synthesis, respectively. Thus, glutathionylation at the 2-fluoromethyl group is responsible for the radiodefluorination of [(18)F]SP203 in rat. This study provides the first demonstration of glutathione-promoted radiodefluorination of a PET radioligand.
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PMID:Radiodefluorination of 3-fluoro-5-(2-(2-[18F](fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile ([18F]SP203), a radioligand for imaging brain metabotropic glutamate subtype-5 receptors with positron emission tomography, occurs by glutathionylation in rat brain. 1880 25


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