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 ubiquitous glutathione transferases (GSTs) catalyze glutathione conjugation to many compounds and have other diverse functions that continue to be discovered. We noticed sequence similarities between Omega class GSTs and a nuclear chloride channel, NCC27 (CLIC1), and show here that NCC27 belongs to the GST structural family. The structural homology prompted us to investigate whether the human Omega class glutathione transferase GSTO1-1 forms or modulates ion channels. We find that GSTO1-1 modulates ryanodine receptors (RyR), which are calcium channels in the endoplasmic reticulum of various cells. Cardiac RyR2 activity was inhibited by GSTO1-1, whereas skeletal muscle RyR1 activity was potentiated. An enzymatically active conformation of GSTO1-1 was required for inhibition of RyR2, and mutation of the active site cysteine (Cys-32 --> Ala) abolished the inhibitory activity. We propose a novel role for GSTO1-1 in protecting cells containing RyR2 from apoptosis induced by Ca(2+) mobilization from intracellular stores.
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PMID:The glutathione transferase structural family includes a nuclear chloride channel and a ryanodine receptor calcium release channel modulator. 1103 31

Omega class glutathione transferase (GSTO) has been recently described in a number of mammalian species. We used immunohistochemistry to determine the cellular and tissue distribution of GSTO1-1 in humans. Expression of GSTO1-1 was abundant in a wide range of normal tissues, particularly liver, macrophages, glial cells, and endocrine cells. We also found nuclear staining in several types of cells, including glial cells, myoepithelial cells of the breast, neuroendocrine cells of colon, fetal myocytes, hepatocytes, biliary epithelium, ductal epithelium of the pancreas, Hoffbauer cells of the placenta, and follicular and C-cells of the thyroid. These observations and the known activity of GSTO1-1 suggest biological functions that are not shared with other GSTs.
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PMID:Immunohistochemistry of omega class glutathione S-transferase in human tissues. 1145 26

The drinking of water containing large amounts of inorganic arsenic is a worldwide major public health problem because of arsenic carcinogenicity. Yet an understanding of the specific mechanism(s) of inorganic arsenic toxicity has been elusive. We have now partially purified the rate-limiting enzyme of inorganic arsenic metabolism, human liver MMA(V) reductase, using ion exchange, molecular exclusion, and hydroxyapatite chromatography. When SDS-beta-mercaptoethanol-PAGE was performed on the most purified fraction, seven protein bands were obtained. Each band was excised from the gel, sequenced by LC-MS/MS and identified according to the SWISS-PROT and TrEMBL Protein Sequence databases. Human liver MMA(V) reductase is 100% identical, over 92% of sequence that we analyzed, with the recently discovered human glutathione-S-transferase Omega class hGSTO 1-1. Recombinant human GSTO1-1 had MMA(V) reductase activity with K(m) and V(max) values comparable to those of human liver MMA(V) reductase. The partially purified human liver MMA(V) reductase had glutathione S-transferase (GST) activity. MMA(V) reductase activity was competitively inhibited by the GST substrate, 1-chloro 2,4-dinitrobenzene and also by the GST inhibitor, deoxycholate. Western blot analysis of the most purified human liver MMA(V) reductase showed one band when probed with hGSTO1-1 antiserum. We propose that MMA(V) reductase and hGSTO 1-1 are identical proteins.
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PMID:Human monomethylarsonic acid (MMA(V)) reductase is a member of the glutathione-S-transferase superfamily. 1151 Nov 79

Glutathione S-transferases (EC 2.5.1.18) (GSTs), are a family of multifunctional enzymes present in all living organisms whose main function is the detoxification of electrophilic compounds. GSTs are considered the most prominent detoxifying class II enzymes in helminths. We describe here the characterization of novel dehydroascorbate reductase and thiol transferase activities that reside in the human parasite Schistosoma mansoni GSTx. Protein sequence analysis of this parasite product showed lower identity to known GSTs. However, phylogenic analysis placed SmGSTx among the recently described omega class GSTs (GSTO1-1). We report here that SmGSTO protein is a 28-kDa polypeptide, detected in all life stages of the parasite, being highly expressed in adult worms. Like other omega class GSTs, SmGSTO showed very low activity toward classical GSTs substrates as 1-chloro-2,4-dinitrobenzene, and no binding affinity to glutathione-agarose matrix but showed some biochemical characteristics related with thioredoxins/glutaredoxins. Interestingly, SmGSTO was able to bind S-hexyl glutathione matrix and displayed significant glutathione-dependent dehydroascorbate reductase and thiol transferase enzymatic activities.
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PMID:Characterization of an omega-class glutathione S-transferase from Schistosoma mansoni with glutaredoxin-like dehydroascorbate reductase and thiol transferase activities. 1242 49

Glutathione-S-transferase class Omega (GSTO 1-1) belongs to a new subfamily of GSTs, which is identical with human monomethylarsonic acid (MMA(V)) reductase, the rate limiting enzyme for biotransformation of inorganic arsenic, environmental carcinogen. Recombinant GSTO 1-1 variants (Ala140Asp and Thr217Asn) were functionally characterized using representative substrates. No significant difference was observed in GST activity towards 1-chloro-2,4-dinitrobenzene, whereas thioltransferase activity was decreased to 75% (Ala140Asp) and 40% (Thr217Asn) of the wild-type GSTO 1-1. For MMA(V) reductase activity, the Ala140Asp variant exhibited similar kinetics to wild type, while the Thr217Asn variant had lower V(max) (56%) and K(m) (64%) values than the wild-type enzyme. The different activities of the enzyme variants may influence both the intracellular thiol status and arsenic biotransformation. This can help explain the variation between individuals in their susceptibility to oxidative stress and inorganic arsenic.
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PMID:Functional characterization of two variant human GSTO 1-1s (Ala140Asp and Thr217Asn). 1256 92

A new class of glutathione S-transferase enzymes named omega (GSTO) has been recently identified and shown to be expressed in a wide range of human tissues. A genetic polymorphism of the GSTO1 gene causing an alanine-to-aspartate (A140D) substitution in amino acid 140 produces a variant with lowered enzyme activities in the biotransformation of inorganic arsenic, a common contaminant of drinking water in many regions of the world and a well-known carcinogen. In order to investigate the role of GSTO1 inheritance pattern on thyroid cancer risk we used a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-sequencing approach to compare the genotypes of 173 (87 women, 86 men; 18-81 years old; 47+/-18 years old) healthy control individuals with those of 145 patients with thyroid nodules (84 women, 61 men; 17-81 years old; 49+/-14 years old) including 17 follicular carcinomas, 76 papillary carcinomas, 21 follicular adenomas and 31 multinodular goiters. The incidence of GSTO1 variants was similar in the control population and population with the benign and malignant nodules. There was no association between genotype and the patients' clinical features, tumour parameters of aggressiveness at diagnosis or behaviour during follow-up. We conclude that GSTO1 variants do not influence the risk for thyroid nodules or their pathologic and clinical characteristics.
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PMID:GSTO polymorphism analysis in thyroid nodules suggest that GSTO1 variants do not influence the risk for malignancy. 1590 98

The class of Omega glutathione transferases is newly identified with novel structural and functional characteristics. Human GSTO 1-1 (glutathione S-transferase Omega 1) is the first member of the GST Omega class. It was found to play a role in apoptosis and be in association with age-at-onset of AD and PD. In order to improve the understanding of the properties of other Omega class members, we screened a human fetal brain cDNA library and obtained the human GSTO2 (glutathione S-transferase Omega 2) cDNA. The full-length cDNA of human GSTO2 is 1179 bp long and encodes a protein of 243 amino acid residues. Expression pattern analysis revealed that GSTO2 was ubiquitously expressed at a low level, with a higher expression in pancreas and prostate. Enzyme assays showed that GSTO2 protein had activities similar to Omega class GSTs. It has detectable glutathione-dependent thiol transferase activity and glutathione-dependent dehydroascorbate reductase activity. But different from GSTO1-1, GSTO2 exhibits a high catalytic activity with CDNB. Subcellular localization analysis of GSTO2-EGFP fusion protein revealed that GSTO2 distributed to cytoplasm of COS-7 cells and both cytoplasm and nucleus of L-02, QGY-7703 and SMMC-7721 cells. Overexpression of GSTO2 induced apoptosis of L-02 cells detected by Annexin V-PE staining. The results suggest that GSTO2 may play an important role in cellular signaling.
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PMID:Cloning, expression and characterization of human glutathione S-transferase Omega 2. 1594 73

There are two functional Omega class glutathione transferase (GST) genes in humans. GSTO1 is polymorphic with several coding region alleles, including an A140D substitution, a potential deletion of E155 and an E208K substitution. GSTO2 is also polymorphic with an N142D substitution in the coding region. We investigated the effect of these variations on the enzyme's thioltransferase, dehydroascorbate reductase, monomethylarsonate reductase and dimethylarsonate reductase activities. Variant proteins were expressed in Escherichia coli and purified by Ni-agarose affinity chromatography. GSTO2-2 was insoluble and had to be dissolved and refolded from 8 M urea. The A140D and E208K substitutions in GSTO1-1 did not alter specific activity. The deletion of E155 caused a two- to three-fold increase in the specific activity with each substrate. This deletion also caused a significant decrease in the enzyme's heat stability. The E155 deletion has been linked to abnormal arsenic excretion patterns; however, the available data do not clearly identify the cause of this abnormality. We found that GSTO2-2 has activity with the same substrates as GSTO1-1, and the dehydroascorbate reductase activity of GSTO2-2 is approximately 70-100-fold higher than that of GSTO1-1. The polymorphic N142D substitution had no effect on the specific activity of the enzyme with any substrate. The most notable feature of GSTO2-2 was its very high dehydroascorbate reductase activity, which suggests that GSTO2-2 may significantly protect against oxidative stress by recycling ascorbate. A defect in ascorbate metabolism may provide a common mechanism by which the Omega class GSTs influence the age-at-onset of Alzheimer's and Parkinson's diseases.
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PMID:Characterization of the monomethylarsonate reductase and dehydroascorbate reductase activities of Omega class glutathione transferase variants: implications for arsenic metabolism and the age-at-onset of Alzheimer's and Parkinson's diseases. 1597 Jul 97

Polymorphic glutathione S-transferase (GST) genes causing variations in enzyme activity may influence individual susceptibility to cancer. Though polymorphisms have been reported in GSTO1 and GSTO2, their predisposition to cancer risk has not yet been explored. In this case control study, 28 cases of hepatocellular carcinoma, 30 cases of cholangiocarcinoma, 31 cases of colorectal cancer, 30 cases of breast cancer and 98 controls were compared for frequencies of GSTO1 and GSTO2 genotypes. The statistical analysis provided the support for the difference in genotypic distribution for GSTO1*A140D between hepatocellular carcinoma (OR 23.83, CI 95%: 5.07-127), cholangiocarcinoma (OR 8.5, CI 95%: 2.07-37.85), breast cancer (OR 3.71, CI 95%: 1.09-13.02) and control. With regards to GSTO2*N140D polymorphism, there was no difference in genotypic distribution between all the types of cancer and control. The study suggests that GSTO1*A140D polymorphism could play an important role as a risk factor for the development of hepatocellular carcinoma, cholangiocarcinoma and breast cancer.
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PMID:Polymorphism of glutathione S-transferase omega gene and risk of cancer. 1599 93

The Omega class of cytosolic glutathione transferases was initially recognized by bioinformatic analysis of human sequence databases, and orthologous sequences were subsequently discovered in mouse, rat, pig, Caenorhabditis elegans, Schistosoma mansoni, and Drosophila melanogaster. In humans and mice, two GSTO genes have been recognized and their genetic structures and expression patterns identified. In both species, GSTO1 mRNA is expressed in liver and heart as well as a range of other tissues. GSTO2 is expressed predominantly in the testis, although moderate levels of expression are seen in other tissues. Extensive immunohistochemistry of rat and human tissue sections has demonstrated cellular and subcellular specificity in the expression of GSTO1-1. The crystal structure of recombinant human GSTO1-1 has been determined, and it adopts the canonical GST fold. A cysteine residue in place of the catalytic tyrosine or serine residues found in other GSTs was shown to form a mixed disulfide with glutathione. Omega class GSTs have dehydroascorbate reductase and thioltransferase activities and also catalyze the reduction of monomethylarsonate, an intermediate in the pathway of arsenic biotransformation. Other diverse actions of human GSTO1-1 include modulation of ryanodine receptors and interaction with cytokine release inhibitory drugs. In addition, GSTO1 has been linked to the age at onset of both Alzheimer's and Parkinson's diseases. Several polymorphisms have been identified in the coding regions of the human GSTO1 and GSTO2 genes. Our laboratory has expressed recombinant human GSTO1-1 and GSTO2-2 proteins, as well as a number of polymorphic variants. The expression and purification of these proteins and determination of their enzymatic activity is described.
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PMID:Characterization of the omega class of glutathione transferases. 1639 80


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