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)

A chimeric enzyme (GST121) of the human alpha-glutathione S-transferases GST1-1 and GST2-2, which has improved catalytic efficiency and thermostability from its wild-type parent proteins, has been crystallized in a space group that is isomorphous with that reported for crystals of GST1-1. However, a single-site (G82R) mutant of GST121, which exhibits a significant reduction both in vitro and in vivo in protein thermostability, forms crystals that are not isomorphous with GST1-1. The mutant protein crystallizes in space group P2(1)2(1)2(1), with cell dimensions a = 49.5, b = 92.9, c = 115.9 A, and one dimer per asymmetric unit. Preliminary crystallographic results show that a mutation of the surface residue Gly 82 from a neutral to a charged residue causes new salt bridges to be formed among the GST dimers, suggesting that the G82R mutant might aggregate more readily than does GST121 in solution, resulting in a change of its solution properties.
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PMID:A surface mutant (G82R) of a human alpha-glutathione S-transferase shows decreased thermal stability and a new mode of molecular association in the crystal. 789 74

Onchocerca volvulus is a pathogenic human filarial parasite which, like other helminth parasites, is capable of evading the host's immune responses by a variety of defense mechanisms which are likely to include the detoxification and repair mechanisms of the enzyme glutathione S-transferase (GST). In this study, we show that one of the previously described GSTs from O. volvulus appears to possess the characteristics of a secreted enzyme. When the complete O. volvulus GST1 (OvGST1) sequence presented here is compared with those of other GSTs, 50 additional residues at the N terminus are observed, the first 25 showing characteristics of a signal peptide. This is consistent with the N-terminal sequence data on the native mature enzyme which begins at amino acid 26, based on the deduced protein sequence from the cDNA. The native protein, without the signal peptide sequence, possesses a 24-amino-acid extension not present in other GSTs. The deduced amino acid sequence of the OvGST1 cDNA clone was shown to possess four potential N-glycosylation sites. Digestion of O. volvulus homogenate with endoglycosidase, followed by detection of OvGST1 with specific antibody, indicated that the enzyme possesses at least two N-linked oligosaccharide chains. Gel filtration of the Escherichia coli-produced recombinant OvGST1 showed that it is enzymatically active as a nonglycosylated dimer. OvGST1 is found in the media surrounding adult worms maintained in culture, indicating that, in vitro, this enzyme is released from the worm. The strongest immunostaining for OvGST1 was observed in the outer cellular covering of the adult worm body, the syncytial hypodermis, especially in the interchordal hypodermis, where the peripheral membrane forms a series of lamellae which run into the outer zone of the hypodermal cytoplasm.
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PMID:A novel type of glutathione S-transferase in Onchocerca volvulus. 792 52

Aromatic DNA adducts in total white blood cells, cytochrome P450 (CYP) class 1A1 and glutathione transferase (GST1) class mu genotypes and micronuclei in T- and B-lymphocytes were studied in 69 full-time chimney sweeps and 35 controls, all male subjects. The sweeps had a higher (22%) but statistically non-significant increase in the level of DNA adducts as compared to the controls when all individuals independent of genotype were compared. The non-inducible CYP1A1 genotype, m1/m1, lacking a MspI restriction site at the 3' end of the gene, was associated with significantly higher adduct levels in the sweeps. Among the 26 sweeps with the combined genotype m1/m1 and GST1(-), a statistically significant 60% increase in median adduct levels was observed as compared with those 14 control subjects with the corresponding genotype. Smoking also showed a significant effect on the level of adducts. The effect on DNA adducts by sweeping, smoking and genotype appeared to be additive and independent of each other. DNA adducts in sweeps were moderately but statistically significantly correlated with micronuclei in both T- and B-lymphocytes. The correlation between adduct levels and micronuclei was most marked in T-lymphocytes of individuals lacking the GST1 gene.
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PMID:Aromatic DNA adducts, micronuclei and genetic polymorphism for CYP1A1 and GST1 in chimney sweeps. 803 10

A close correlation between cigarette smoking associated lung cancer incidence and an Msp I restriction fragment length polymorphism (RFLP) of the human P-450 1A1 (CYP1A1) gene was found in a Japanese population in terms of genotype frequency and cigarette dose. A Val/Ile codon difference in the primary structure of the CYP1A1 protein (Val-, Ile-type) was in linkage disequilibrium with the Msp I RFLP. A synergistic increase in susceptibility to lung cancer was found when combining genotyping of CYP1A1 and the Mu-class of glutathione S-transferase (GST1). Interindividual variability in the genetic make-up of carcinogen metabolizing enzymes may thus be a key host factor to explain the differences in susceptibility to chemical carcinogenesis among individuals.
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PMID:The CYP1A1 gene and cancer susceptibility. 810 89

Three glutathione S-transferases from Lucilia cuprina (Australian sheep blowfly) pupae were purified by affinity chromatography and anion-exchange chromatography. One isoenzyme was composed of M(r)-24,800 subunits, and two isoenzymes had subunits of M(r) 23,900. The M(r)-23,900 subunits showed immunological identity and were immunologically distinct from the M(r)-24,800 subunits. All three enzymes were active with the substrate 1-chloro-2,4-dinitrobenzene and had low activity with 1,2-dichloro-4-nitrobenzene. A cDNA clone encoding a M(r)-23,900 subunit (LuGST1) was isolated and sequenced. The sequence has close similarities (> 81%) to that of GSTs from the fruitfly Drosophila melanogaster and Musca domestica (housefly). The deduced amino acid sequence of the Lu GST1 subunit showed no significant similarity to that of the mammalian GSTs to the Alpha, Mu and Pi classes, but shows some similarity (33%) over the first 100 residues with the rat subunit 12 Theta-class GST. Southern blots of genomic DNA hybridized with the LuGST1 cDNA identified many hybridizing fragments. Taken together, these data indicated that the L. cuprina genome contains multiple glutathione S-transferase genes.
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PMID:Purification, molecular cloning and heterologous expression of a glutathione S-transferase from the Australian sheep blowfly (Lucilia cuprina). 817 3

An association of lung cancer susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene was reported in our previous study. This polymorphism has been subsequently found to be closely linked to another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of P4501A1. We report here that genetic risk for squamous cell carcinoma of the lung was associated with these two polymorphisms of the CYP1A1 gene in terms of genotype frequencies and cigarette-smoking dose and that a more increased risk was observed for the individuals with "susceptible" genotypes of CYP1A1 combined with a deficient genotype of a mu-class glutathione S-transferase (GST1), which detoxifies the electrophilic metabolites of aromatic hydrocarbon procarcinogens activated by P4501A1. We first compared the total amounts of cigarettes consumed during a lifetime among 85 patients with squamous cell carcinoma of the lung, whose CYP1A1 and GST1 genes were identified. The patients with a susceptible homozygote of each of the MspI and Ile-Val polymorphisms contracted the carcinoma after smoking fewer cigarettes than those with other genotypes. When the GST1 polymorphism was taken into account, the cumulative cigarette amounts in combined genotyping of the two genes showed distinct differences, resulting in the lowest cigarette dose observed for the patients with a susceptible MspI or Ile-Val genotype of CYP1A1 combined with a deficient GST1 homozygote. Next, a case-control study revealed that the individuals with the susceptible MspI or Ile-Val genotype combined with deficient GST1 were at remarkably high risk with an odds ratio of 16.00 or 41.00, respectively (95% confidence interval, 3.76-68.02 or 8.68-193.61, respectively), at a low dose level of cigarette smoking.
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PMID:Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population. 831 7

In this paper we present the structural analysis of two tightly linked genes from the glutathione S-transferase (GST) gene family in carnation (Dianthus caryophyllus). Southern blot analysis and restriction endonuclease mapping revealed a single cloned region of the carnation genome was highly homologous to the previously characterized ethylene-responsive GST mRNA expressed in flower petals during senescence. Nucleotide sequencing of this region revealed the presence of two tandemly arranged genes designated GST1 and GST2. Comparison of the nucleotide sequences of the cloned genomic region with the previously characterized GST cDNA clone pSR8 revealed that GST1 contains the entire transcription unit in 10 exons interrupted by 9 introns. The transcription unit of GST2 was found to be very similar to GST1 with complete conservation of intron position. In addition, the length and nucleotide sequences of the two genes' introns were highly conserved. GST2 was not completely represented by the cloned genomic region, missing the 3' portion of the transcription unit. Primer extension analysis indicated a single transcriptional start site for transcripts which accumulate in senescing carnation petals. The 5'-flanking sequences of GST1 and GST2 were compared and regions of homology and divergence identified. These upstream sequences were compared with other plant ethylene-responsive genes and GST genes and several sequence motifs of potential importance in the regulation of GST expression were identified. A chimeric gene constructed between -1457 bp of the 5'-flanking DNA of GST1 and the coding region of beta-glucuronidase was found to confer ethylene-inducible expression in flower petals following delivery of the construct into tissue by particle bombardment.
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PMID:Characterization of an ethylene-responsive glutathione S-transferase gene cluster in carnation. 849 18

The rat theta class glutathione S-transferase (GST) 5-5 has been shown to affect the mutagenicity of halogenated alkanes and epoxides. In Salmonella typhimurium TA1535 expressing the rat GST5-5 the number of revertants was increased compared to the control strain by CH2Br2, ethylene dibromide (EDB) and 1,2,3,4-diepoxybutane (BDE); in contrast, mutagenicity of 1,2-epoxy-3-(4'-nitro-phenoxy)propane (EPNP) was reduced. S.typhimurium TA1535 cells were transformed with an expression plasmid carrying the cDNA of the human theta ortholog GST1-1 either in sense or antisense orientation, the latter being the control. These transformed bacteria were utilized for mutagenicity assays. Mutagenicity of EDB, BDE, CH2Br2, epibromohydrin and 1,3-dichloroacetone was higher in the S.typhimurium TA1535 expressing GSTT1-1 than in the control strain. The expression of active enzyme did not affect the mutagenicity of 1,2-epoxy-3-butene or propylene oxide. GSTT1-1 expression reduced the mutagenicity of EPNP. Glutathione S-transferase 5-5 and GSTT1-1 modulate genotoxicity of several industrially important chemicals in the same way. Polymorphism of the GSTT1 locus in humans may therefore cause differences in cancer susceptibility between the two phenotypes.
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PMID:Human glutathione S-transferase T1-1 enhances mutagenicity of 1,2-dibromoethane, dibromomethane and 1,2,3,4-diepoxybutane in Salmonella typhimurium. 856 28

The aim of this study was to investigate the early effects of cephaloridine (CPH) on glutathione-dependent phase II detoxification in the rat proximal tubular cell and to find an in vitro alternative to the in vivo model. The in vivo study was conducted in three groups of rats which received CPH at doses of 250, 500 or 750 mg/kg per day for 3 days, while another group received 500 mg/kg as a single dose. For the in vitro study, rat renal proximal tubular cultured cells were exposed to CPH at concentrations of 0.3, 0.6, 1, 1.7 mM for 24, 48 and 72 h. Glutathione-dependent detoxification was evaluated in vivo and in vitro on the basis of total intracellular glutathione (GSH), glutathione S-transferase (GST) and glutathione peroxidase (GPX). Glutathione reductase (GRED) and GST mRNA levels were also determined. Results of in vivo and in vitro models were comparable in terms of the early increase of GSH, GST and GRED. This increase had a bell-shaped dose-response with a maximum at 500 mg/kg in vivo and 1 mM in vitro. Beyond these doses, GSH and its dependent enzyme levels decreased, associated with cytotoxicity in vitro and renal insufficiency in vivo. The increased GST activity was associated with an increased level of GST7 in vivo and a markedly increased level of GST1-2 in vitro. We concluded that the in vitro model can be used as an alternative to animal experimentation to study glutathione-dependent detoxication. Low cytotoxic doses of CPH induced an early increase of glutathione phase II-dependent detoxification enzymes.
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PMID:Impact of cephaloridine on glutathione and related enzymes: comparison of in vivo and in vitro rat models. 877 82

Ethylene transcriptionally activates a glutathione S-transferase gene (GST1) at the onset of the senescence program in carnation (Dianthus caryophyllus L.) flower petals. A 126 bp region of the GST1 promoter sequence has been identified as an ethylene-responsive enhancer element (ERE). In this paper, we demonstrate the ability of nuclear proteins from senescing petals to recognize a 22 bp sequence within the ERE (ERE oligonucleotide). Mutation of the ERE oligonucleotide sequence significantly alters the strength of this nuclear protein-DNA association. The wild-type ERE oligonucleotide sequence was used to isolate a cDNA clone encoding a sequence-specific DNA binding protein. Nucleotide sequencing and deduced amino acid sequence analysis of this cDNA predicted a 32 kDa protein which we have designated carnation ethylene-responsive element-binding protein-1 (CEBP-1). The mRNA expression pattern of CEBP-1 suggests that it is not transcriptionally regulated by ethylene. The amino acid sequence homology of CEBP-1 with other plant nucleic acid binding proteins indicates a conserved nucleic acid binding domain. Within this domain are two highly conserved RNA-binding motifs, RNP-1 and RNP-2. An acidic region and a putative nuclear localization signal are also identified.
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PMID:Cloning of a DNA-binding protein that interacts with the ethylene-responsive enhancer element of the carnation GST1 gene. 880 6


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