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 planktonic copepod Calanus finmarchicus is a key species in the Northern Atlantic food web; an oceanic area with extensive oil production. Naphthalene is one of the major constituents of produced water and water soluble fractions of petrogenic oils. This study investigates the effects on gene transcription of a short term exposure to naphthalene at levels well below LC(50) concentrations. This was done in order to establish a molecular basis of naphthalene toxicity in a species which has previously been subject only to very limited studies at the molecular level. Naphthalene exposure to C. finmarchicus was found to cause glutathione S-transferase (GST) induction, indicating lipid peroxidation as the major mode of naphthalene toxicity. There is no clear evidence that the putative cytochrome P450 enzymes CYP1A2 and CYP330A1 mRNAs are parts of a detoxification enzyme system. Instead, an observed decrease in CYP330A1 mRNA levels at the highest naphthalene exposure concentration may indicate an effect on ecdysteroidogenesis. Only the lowest naphthalene concentration lead to increased mRNA levels of antioxidants SOD and CAT, indicating no clear evidence for general cellular oxidative stress following exposure. Small and insignificant changes in the HSP-70, HSP-90 and ubiquitin mRNA levels indicate a small degree of protein damage owing to naphthalene exposure. The established culture of C. finmarchicus at the SINTEF/NTNU Sealab, and the use of gene transcription analyses provide excellent tools for improving the understanding of biochemical mechanisms involved in the defense against environmental impacts and the molecular modes of toxicity in this species.
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PMID:Effects of naphthalene on gene transcription in Calanus finmarchicus (Crustacea: Copepoda). 1805 6

The present study reports the first analysis of water pollutants in Sri Lankan waters using a suite of biomarkers in Nile tilapia (Oreochromis niloticus) residing in Bolgoda Lake which receives urban, industrial and domestic wastes from multiple sources. The fish were collected from the lake in the dry period (April 2005) and wet periods (September 2005, October 2006) and the levels of biomarkers viz. hepatic ethoxyresorufin O-deethylase (EROD), glutathione S-transferase (GST), metallothioneins, biliary fluorescent aromatic compounds, brain and muscle cholinesterases (ChE) were compared with those of the laboratory reared control fish and the fish obtained from a less polluted water body, Bathalagoda reservoir (reference site). The results revealed that biomarker levels of the fish collected from the reference site were not significantly different from the controls. Hepatic EROD and GST activities in fish from Bolgoda Lake were induced 4.2-16.6 folds and 1.4-3.3 folds respectively compared with the control fish. Analysis of bile in the lake fish revealed recent uptake of naphthalene, pyrene and benzo(a)pyrene type polycyclic aromatic hydrocarbons (PAHs). The induction of EROD activities in feral fish reflects the exposure of fish to aryl hydrocarbon receptor agonists including PAHs present as pollutants in the Bolgoda Lake. Cholinesterase activity in the fish inhabiting one sampling site of Bolgoda Lake was lower (22-40% inhibition) than the activity measured in the control fish indicating the presence of anticholinesterase pollutants in the area. Hepatic metallothionein levels in the lake fish were higher (1.9-3.2 folds) in comparison to the controls indicating metal exposure. The results support the potential use of these biomarkers in Nile tilapia in assessing pollution in tropical water bodies.
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PMID:Use of biomarkers in Nile tilapia (Oreochromis niloticus) to assess the impacts of pollution in Bolgoda Lake, an urban water body in Sri Lanka. 1868 34

Maleyl pyruvate isomerase (MPI) is a bacterial glutathione S-transferase (GST) from the pathway for degradation of naphthalene via gentisate that enables the bacterium Ralstonia to use polyaromatic hydrocarbons as a sole carbon source. Genome sequencing projects have revealed the presence of large numbers of GSTs in bacterial genomes, often located within gene clusters encoding the degradation of different aromatic compounds. This structure is therefore an example of this under-represented class of enzymes. Unlike many glutathione transferases, the reaction catalysed by MPI is an isomerisation of an aromatic ring breakdown product, and glutathione is a true cofactor rather than a substrate in the reaction. We have solved the structure of the enzyme in complex with dicarboxyethyl glutathione, an analogue of a proposed reaction intermediate, at a resolution of 1.3 A. The structure provides direct evidence that the glutathione thiolate attacks the substrate in the C2 position, with the terminal carboxylate buried at the base of the active site cleft. Our structures suggest that the C1-C2 bond remains fixed so when rotation occurs around the C2-C3 bond the atoms from C4 onwards actually move. We identified a conserved arginine that is likely to stabilize the enolate form of the substrate during the isomerisation. Arginines at either side of the active site cleft can interact with the end of the substrate/product and preferentially stabilise the product. MPI has significant sequence similarity to maleylacetoacetate isomerase (MAAI), which performs an analogous reaction in the catabolism of phenylalanine and tyrosine. The proposed mechanism therefore has relevance to the MAAIs. Significantly, whilst the overall sequence identity is 40% only one of the five residues from the Zeta motif in the active site is conserved. We re-examined the roles of the residues in the active site of both enzymes and the Zeta motif itself.
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PMID:Structure of bacterial glutathione-S-transferase maleyl pyruvate isomerase and implications for mechanism of isomerisation. 1882 4

With the acute toxicity test, we obtained the median lethal concentration (LC50) of naphthalene to the zebrafish for 96 h, which was 11.8 mg x L(-1). Then we set up five treatments(0, 1/6 LC50, 1/4 LC50, 1/3 LC50 and 1/2 LC50) and exposed zebrafish to these treatments for 0.5, 1, 2, 4, 7 and 14d respectively to study the effects of naphthalene on the antioxidant defense system in visceral mass of zebrafish. The results showed that GSH, GPx and GST were very sensitive to naphthalene and were inhibited or induced at 0.5 d exposure. The activities of GPx were induced on the whole after 0.5 d, but were inhibited at higher concentration treatments (1/3 LC50 and 1/2 LC50 treatments) at 14 d exposure; while the activities of GST and the contents of GSH were almost lower than that of the control. The activities of SOD were induced first and then inhibited after 2 d; the activities of CAT were inhibited almost in the all treatments after 1 d. The effects of naphthalene on the antioxidant defense system in visceral mass of zebrafish could be used as biomarkers to estimate the biological effect of fish exposed to polycyclic aromatic hydrocarbons.
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PMID:[Stress and biological response of naphthalene on the antioxidant defense system in visceral mass of zebrafish (Danio rerio)]. 1940 9

Pseudomonas putida GJ31 has been reported to grow on chlorobenzene using a meta-cleavage pathway with chlorocatechol 2,3-dioxygenase (CbzE) as a key enzyme. The CbzE-encoding gene was found to be localized on the 180 kb plasmid pKW1 in a cbzTEXGS cluster, which is flanked by transposases and encodes only a partial (chloro)catechol meta-cleavage pathway comprising ferredoxin reductase, chlorocatechol 2,3-dioxygenase, an unknown protein, 2-hydroxymuconic semialdehyde dehydrogenase and glutathione S-transferase. Downstream of cbzTEXGS are located cbzJ, encoding a novel type of 2-hydroxypent-2,4-dienoate hydratase, and a transposon region highly similar to Tn5501. Upstream of cbzTEXGS, traNEOFG transfer genes were found. The search for gene clusters possibly completing the (chloro)catechol metabolic pathway of GJ31 revealed the presence of two additional catabolic gene clusters on pKW1. The mhpRBCDFETP cluster encodes enzymes for the dissimilation of 2,3-dihydroxyphenylpropionate in a novel arrangement characterized by the absence of a gene encoding 3-(3-hydroxyphenyl)propionate monooxygenase and the presence of a GntR-type regulator, whereas the nahINLOMKJ cluster encodes part of the naphthalene metabolic pathway. Transcription studies supported their possible involvement in chlorobenzene degradation. The upper pathway cluster, comprising genes encoding a chlorobenzene dioxygenase and a chlorobenzene dihydrodiol dehydrogenase, was localized on the chromosome. A high level of transcription in response to chlorobenzene revealed it to be crucial for chlorobenzene degradation. The chlorobenzene degradation pathway in strain GJ31 is thus a mosaic encoded by four gene clusters.
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PMID:Degradation of chloroaromatics by Pseudomonas putida GJ31: assembled route for chlorobenzene degradation encoded by clusters on plasmid pKW1 and the chromosome. 1974 88

Despite ubiquity of polycyclic aromatic hydrocarbons (PAHs) in the tropical environments, little information is available concerning responses of tropical fish to PAHs and associated toxicity. In the present study, effects of five PAHs containing two to four aromatic rings on hepatic CYP1A dependent ethoxyresorufin O-deethylase (EROD), glutathione S-transferase (GST) and serum sorbitol dehydrogenase (SDH) activities in Nile tilapia, a potential fish species for biomonitoring pollution in tropical waters, were evaluated. Results showed that EROD activities were induced by the PAHs containing four aromatic rings (pyrene and chrysene) in a dose dependent manner. However PAHs with two to three aromatic rings (naphthalene, phenanthrene and fluoranthene) caused no effect or inhibition of EROD activities depending on the dose and the duration. Fluoranthene was the most potent inhibitor. SDH results demonstrated that high doses of fluoranthene induced hepatic damage. GST activity was induced by the lowest dose of phenanthrene, fluoranthene and chrysene but high doses had no effect. The results indicate that induction of EROD enzyme in Nile tilapia is a useful biomarker of exposure to PAHs such as pyrene and chrysene. However EROD inhibiting PAHs such as fluoranthene in the natural environment may modulate the EROD inducing potential of other PAHs thereby influencing PAH exposure assessments.
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PMID:Modulation of ethoxyresorufin O-deethylase and glutathione S-transferase activities in Nile tilapia (Oreochromis niloticus) by polycyclic aromatic hydrocarbons containing two to four rings: implications in biomonitoring aquatic pollution. 2022 26

The in vitro bioactivation of the selective serotonin and norepinephrine reuptake inhibitor duloxetine was investigated using liver microsomes and cytosol, expressed glutathione transferase, and recombinant P450 2D6 and 1A2. In the presence of glutathione, several conjugates were identified and characterized using a combination of direct infusion nanoelectrospray mass spectrometry on an LTQ/Orbitrap and liquid-chromatography mass spectrometry on a triple quadrupole. Structural characterization of these conjugates revealed that glutathione conjugation occurred on naphthalene rather than on thiophene and likely proceeded via a reactive epoxide intermediate. Experiments with recombinant P450s and the isoform specific inhibitors quinidine and furafylline suggested that both P450 2D6 and 1A2 were involved in the bioactivation of duloxetine. To explore the utility of in silico approaches to address bioactivation issues, MetaSite and two docking approaches (rigid and induced-fit docking) utilizing publicly available human P450 crystal structures or a homology model for P450 2C19 were used to predict the sites of bioactivation for duloxetine as well as the thiophene containing compounds tienilic acid, suprofen, ticlopidine, methapyrilene, and OSI-930 for which glutathione conjugates on the thiophene moiety have been reported. MetaSite and induced fit docking but not rigid docking correctly predicted that naphthalene rather than thiophene was the preferred site of bioactivation for duloxetine by P450 2D6. MetaSite predictions were also consistent with literature reports that thiophene was the site of glutathione conjugation for tienilic acid, suprofen, and OSI-930 but not for ticlopidine or methapyrilene. Of the two docking approaches investigated, induced fit docking results were consistent with thiophene as the site of bioactivation for all compounds to which it was applied. In conclusion, our investigation identified the likely bioactivation pathway for duloxetine and demonstrated the utility of in silico approaches MetaSite and induced fit docking to address potential bioactivation liabilities.
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PMID:Characterization of glutathione conjugates of duloxetine by mass spectrometry and evaluation of in silico approaches to rationalize the site of conjugation for thiophene containing drugs. 2066 86

Relations between several stress oxidative biomarkers and aromatic polycyclic hydrocarbon (PAH) concentrations have been studied in wild sole, Solea senegalensis collected in the vicinity of a petrochemical industry. Antioxidant enzyme activities in eco-toxicological studies constitute excellent markers for exposure to a large variety of pollutants. The 16 PAHs in sediment as well as oxidative damage (LPO), activity of catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and PAHs type metabolites in sole liver were analysed. Significant correlations (p<0.05) were established between some biomarkers as GST, GPx and CAT and PAHs metabolites in liver (naphthalene, pyrene and phenanthrene) and PAHs concentrations in sediments (fluoranthene, acenaphthene, anthracene and chrysene). PAHs accumulated in the sediment and organisms are inducers of antioxidant defences. GST, GPx and CAT were robust biomarkers showing correlations with both PAHs in sediments and liver PAH metabolites showing different responses to low and high molecular weight PAHs.
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PMID:Biochemical effects and polycyclic aromatic hydrocarbons (PAHs) in senegal sole (Solea senegalensis) from a Huelva estuary (SW Spain). 2084 49

OsGSTL2, encoding glutathione S-transferase, is a lambda class gene on chromosome 3 of rice (Oryza sativa L.). RNA blot analysis and semi-quantitative RT-PCR assays demonstrated that the transcription of OsGSTL2 in rice roots treated with chlorsulfuron increased significantly. To further understand OsGSTL2 promoter activity, a DNA fragment (GST2171) of 2,171 bp upstream of the OsGSTL2 coding region was isolated. In silico sequence analysis revealed that this fragment contains stress-regulated regulatory elements, hormone-responsive elements and three transposable elements. To define the core promoter sequence, a series of 5' truncation derivatives of GST2171 were fused to uidA gene. The chimeric genes were introduced into rice plants via Agrobacterium-mediated transformation. The expression of the GST2171::GUS transgene varied considerably. GUS staining indicated that the uidA gene is expressed in young seedlings, older leaves, flowering glumes and seeds, but not in older roots. Quantitative fluorescence assays revealed that the expression of the uidA gene is strong in young seedlings and decreases gradually over a period of 25 days. To our surprise, among the 5' truncation derivatives, the shortest promoter GST525 showed the highest GUS expression, and the second shortest promoter GST962 showed the lowest GUS expression. The uidA gene expression in the roots of transgenic rice seedlings is upregulated by chlorsulfuron, glyphosate, salicylic acid (SA) and naphthalene acetic acid (NAA). The possible roles of the repetitive elements on the OsGSTL2 promoter were discussed in terms of transcription repression and promoter induction by herbicides and hormones.
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PMID:Isolation and characterization of a rice glutathione S-transferase gene promoter regulated by herbicides and hormones. 2115 26

Eleven 1,4-naphthoquinone analogues with different amino substitutions at position 3 of the quinone ring earlier reported for macrofilaricidal activity were selected and screened against purified cytosolic GST isolated from the bovine filarial worm Setaria digitata and IC(50) values were determined. Of the 11 compounds tested, 8 showed good inhibition against S. digitata GST. The IC(50) values of the most effective macrofilaricidal compounds-11 [2-(4-methylpiperazin-1-yl)naphthalene-1,4-dione] and 9 {2-[(1,3-dimethylbutyl)amino]naphthalene -1,4-dione}-were 0.872 and 0.994 mM, respectively. Compounds 9 and 11 were further studied for type of enzyme inhibition and found to exhibit competitive and uncompetitive inhibition kinetics, respectively, with respect to substrate GSH. All 11 compounds were in agreement with Lipinski's rule of five and passed through the FAFDrugs ADME/tox filter. Molecular docking was carried out using the modeled 3D structure of wbGST PDB ID:1SFM as receptor and substituted naphthoquinones as ligands using AutoDock 4.0. The binding energy of nine compounds varied from -9.15 to -6.58 Kcal mol(-1), whereas compounds 8 and 10 did not show any binding to the receptor. Among the compounds studied, compound 7 {2-[3-(diethylamino) propyl]aminonaphthalene-1,4-dione} showed maximum affinity towards wbGST as it exhibited the lowest binding energy, followed by compounds 11 and 9. However compound 7 was not macrofilaricidal while 11 and 9 exhibited macrofilaricidal activity. The results of in silico and in vitro studies with the synthesized 1,4 -naphthoquinone analogues on filarial GST and in vitro macrofilaricidal activity against adult bovine filarial worm S. digitata open up a promising biochemical target for antifilarial drug development.
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PMID:Studies on filarial GST as a target for antifilarial drug development-in silico and in vitro inhibition of filarial GST by substituted 1,4-naphthoquinones. 2126 50


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