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)

Human muscle glutathione S-transferase isozyme, GST zeta (pI 5.2) has been purified by three different methods using immunoaffinity chromatography, DEAE cellulose chromatography, and isoelectric focusing. GST zeta prepared by any of the three methods does not recognize antibodies raised against the alpha, mu, or pi class glutathione S-transferases of human tissues. GST zeta has a blocked N-terminus and its peptide fingerprints also indicate it to be distinct from the alpha, mu, or pi class isozymes. As compared to GSTs of alpha, mu, and pi classes, GST zeta displays higher activities toward t-stilbene oxide and Leukotriene A4 methyl ester. GST zeta also expresses GSH-peroxidase activity toward hydrogen peroxide. The Kms of GST zeta for CDNB and GSH were comparable to those reported for other human GSTs but its Vmax for CDNB, 7620 mol/mol/min, was found to be considerably higher than that reported for other human GSTs. The kinetics of inhibition of GST zeta by hematin, bile acids, and other inhibitors also indicate that it was distinct from the three classes of GST isozymes. These studies suggest that GST zeta corresponds to a locus distinct from GST1, GST2, and GST3 and probably corresponds to the GST4 locus as suggested previously by Laisney et al. (1984, Human Genet. 68, 221-227). The results of peptide fingerprints and kinetic analysis indicate that as compared to the pi and alpha class isozymes, GST zeta has more structural and functional similarities with the mu class isozymes. Besides GST zeta several other GST isozymes belonging to pi and mu class have also been characterized in muscle. The pi class GST isozymes of muscle have considerable charge heterogeneity among them despite identical N-terminal sequences.
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PMID:Purification and characterization of human muscle glutathione S-transferases: evidence that glutathione S-transferase zeta corresponds to a locus distinct from GST1, GST2, and GST3. 184 34

An acidic glutathione S-transferase (GST) isoenzyme termed GST6 has been isolated from human brain, characterized and compared with other isoenzymes. The N-terminal amino acid sequence of GST6 was found to be identical with that of GST4 previously purified from human muscle. GST6 cross-reacted with antibody raised against GST4, but not with antisera raised against GST1, GST2 or GST3. The subunit Mr and pI of GST6 were found to be different from those of GST4. The present results indicate that GST6 is another member of the Mu evolutionary class which in man also includes GST1, GST4 and GST5. A minor component that co-purified with GST6 was shown to have an N-terminal sequence similar to, but not identical with, that of GST3. This isoenzyme may be an additional member of the Pi evolutionary class.
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PMID:Purification and characterization of acidic glutathione S-transferase 6 from human brain. 200 8

A class-mu glutathione transferase cDNA clone, GTHMUS, was isolated from human myoblasts and its sequence was determined. The sequence predicts a protein of molecular weight 25,599 whose 24 amino-terminal residues are identical to those of the class-mu isoenzyme expressed from the GST4 locus. The GTHMUS cDNA shares 93.7% nucleotide sequence identity with a human liver cDNA clone, GTH411, that is encoded at the GST1 locus. Comparison of the liver and muscle cDNA sequences shows two regions of remarkable sequence conservation: a 140-nucleotide region in the 5' coding portion of the molecule that has a single silent nucleotide substitution, and a 550-nucleotide region, including the entire 3' noncoding region, that has only three nucleotide substitutions or deletions. This sequence conservation suggests that gene conversion has occurred between the human GST1 and GST4 glutathione transferase gene loci. The human muscle and liver glutathione transferase clones GTHMUS and GTH411 have been expressed in Escherichia coli. The kinetic mechanism of the muscle enzyme was examined in product inhibition studies. The inhibition patterns are best modeled by a steady-state ordered bi-bi reaction mechanism. Glutathione is the first substrate bound and chloride ion is the first product released. Chloride ion inhibits the muscle enzyme.
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PMID:Cloning, expression, and characterization of a class-mu glutathione transferase from human muscle, the product of the GST4 locus. 203 81

The active site of glutathione S-transferase isoenzyme 4-4, purified from rat liver, was studied by chemical modification. Tetrachloro-1,4-benzoquinone, a compound previously shown to inactivate glutathione S-transferases very efficiently by covalent binding in or close to the active site, completely prevented the alkylation of the enzyme by iodoacetamide, indicating that the reaction had taken place with cysteine residues. Both from radioactive labeling and spectral quantification experiments, evidence was obtained for the covalent binding of three benzoquinone molecules per subunit, i.e. equivalent to the number of cysteine residues present. This threefold binding was achieved with a fourfold molar excess of the benzoquinone, illustrating the high reactivity of this compound. Comparison of the number of amino acid residues modified by tetrachloro-1,4-benzoquinone with the decrease of catalytic activity revealed an almost complete inhibition after modification of one cysteine residue. Chemical modification studies with diethylpyrocarbonate indicated that all four histidine residues of the subunit are ethoxyformylated in an at least partially sequential manner. Modification of the second histidine residue resulted in complete loss of catalytic activity. Preincubation of the transferase with the glutathione conjugate of tetrachloro-1,4-benzoquinone resulted in 78% protection against this modification. However, glutathione itself hardly protected against the reaction with diethylpyrocarbonate. The intrinsic fluorescence properties of the enzyme were affected by covalent binding of tetrachloro-1,4-benzoquinone. The concentration dependency of the fluorescence quenching is strongly correlated with the inactivation of the enzyme, indicating that covalent binding of the benzoquinone occurs in the vicinity of at least one tryptophan residue. Finally, the binding of bilirubin, as measured by means of circular dichroism, was inhibited by preincubation of the enzyme with tetrachloro-1,4-benzoquinone in a manner which strongly correlated with the loss of enzymatic activity, the protection against inactivation by diethylpyrocarbonate, and the fluorescence quenching. All processes showed a 70-80% decrease after incubation of the enzyme with an equimolar amount of the benzoquinone. Thus, evidence is presented for the presence of a cysteine, a histidine and a tryptophan residue in, or in the vicinity of, the active site of the glutathione S-transferase 4 subunit.
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PMID:Studies on the active site of rat glutathione S-transferase isoenzyme 4-4. Chemical modification by tetrachloro-1,4-benzoquinone and its glutathione conjugate. 271 92

The developmental expression of the basic, near-neutral and acidic isoenzymes of glutathione S-transferase (RX:glutathione R-transferase, EC 2.5.1.18) has been studied in heart and diaphragm. Neither these enzymes nor the putative muscle-specific GST4 isoenzyme demonstrated any developmental trends in expression. In vitro hybridisation and SDS-discontinuous polyacrylamide gel electrophoresis were used to show that the GST4 isoenzyme is a homodimer composed of monomers that have a slightly larger molecular weight than the near-neutral isoenzyme. The sensitivity of GST4 to inhibitors also appeared similar to that of the GST1 2 isoenzyme. Immunodiffusion and immunoblotting techniques were used to show that the acidic enzyme in muscle is immunologically identical to that in other tissues.
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PMID:Studies on the developmental expression of glutathione S-transferase isoenzymes in human heart and diaphragm. 311 98

A total of 168 autopsy liver extracts from Japanese individuals were examined for the glutathione S-transferase (GST) isozymes by means of starch gel electrophoresis. The gene frequencies of GST1*1, GST1*2, and GST1*0 in Japanese were 0.252, 0.057, and 0.691, respectively. GST1*3 was detected as a rare variant allele. The incidence of GST1 0 in 41 liver biopsy samples from patients suffering from various liver diseases was investigated using polyacrylamide gel isoelectric focusing. The GST1 0 phenotype was found more frequently in livers with hepatitis and carcinoma than in control livers. The isozymes coded by different GST loci were partially purified and characterized to study their biochemical properties. The apparent Km values with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate for the isozymes at the GST1, GST2, GST3, and GST4 loci were 604, 1345, 776, and 591 microM, respectively.
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PMID:Liver glutathione S-transferase polymorphism in Japanese and its pharmacogenetic importance. 357 Feb 86

Analysis of different human tissues showed that glutathione S-transferase (GST) of fibroblasts and leucocytes is GST3, an enzyme found in liver extracts by Board (1981). Consequently, the GST localized on human chromosome 11 by Silberstein and Shows (1981, 1982) is GST3. Analysis of tissue extracts showed a new GST band, very intense in muscle extracts and very weak or absent in other tissues, and called GSTM. Analysis of man-rodent hydrids showed synteny between LDHA, GST3, ESA4 and localization of this synteny group on chromosome 11. Analysis of discordant percentages and discordant types between markers favored the following assignments: LDHA on 11p12, GST3 on 11q13 leads to 11qter, ESA on 11q13 leads to 11q22. The present study suggests assignment of GST3 to 11q13 leads to 11q22. Different types of man-rodent hybrids are useful for human gene mapping. A new type hybrid, as used here (nonadhering to glass or plastic surfaces), appears useful because of rapid proliferation and growth in suspension, the latter feature facilitating culture and harvesting.
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PMID:[Localization of the LDHA-GST3-ESA4 synthetic group on human chromosome 11. Analyses of the classic man-rodent hybrids and of a new type (not adhering to the wall)]. 660 88

Molecular modeling techniques have been used to derive a substrate model for class mu rat glutathione S-transferase 4-4 (GST 4-4). Information on regio- and stereoselective product formation of 20 substrates covering three chemically and structurally different classes was used to construct a substrate model containing three interaction sites responsible for Lewis acid--Lewis base interactions (IS1, IS2, and IS3), as well as a region responsible for aromatic interactions (IS4). Experimental data suggest that the first protein interaction site (pIS1, interacting with IS1) corresponds with Tyr115, while the other protein interaction sites (pIS2 and pIS3) probably correspond with other Lewis acidic amino acids. All substrates exhibited positive molecular electrostatic potentials (MEPs) near the site of conjugation with glutathione (GSH), as well as negative MEP values near the position of groups with Lewis base properties (IS1, IS2, or IS3), which interact with pIS1, pIS2, or pIS3, respectively. Obviously, complementarity between the MEPs of substrates and protein in specific regions is important. The substrate specificity and stereoselectivity of GST 4-4 are most likely determined by pIS1 and the distance between the site of GSH attack and Lewis base atoms in the substrates which interact with either pIS2, pIS3, or a combination of these sites. Interaction between aromatic regions in the substrate with aromatic amino acids in the protein further stabilizes the substrate in the active site. The predictive value of the model has been evaluated by rationalizing the conjugation to GSH of 11 substrates of GST 4-4 (representing 3 classes of compounds) which were not used to construct the model. All known metabolites of these substrates are explained with the model. As the computer-aided predictions appear to correlate well with experimental results, the presented substrate model may be useful to identify new potential GST 4-4 substrates.
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PMID:A predictive substrate model for rat glutathione S-transferase 4-4. 754 47

A mu-class glutathione S-transferase (GST) cDNA clone, pHMB1, from rabbit liver has been constructed, using a 748-base-pair fragment of GST Yb1 cDNA as a probe. The nucleotide sequence of pHMB1 has been determined, and the complete amino acid sequence has been deduced. Recombinant clone pHMB1 contains a cDNA insert of 1443 base pairs with 654 nucleotides of open reading frame, 33 nucleotides of 5'-untranslated region, and 756 nucleotides of 3'-untranslated region. The open reading frame encodes a polypeptide (rbGST mu I) comprising 218 amino acids with molecular weight of 25,417. Compared to published mu-class GST sequences, rbGST mu I is 73 and 77% identical to rat Yb1 and human GST4 in amino acid sequence, respectively. The pHMB1 was expressed in Escherichia coli using expression vector pIH821 and the expressed GST was purified as a single band on polyacrylamide gel electrophoresis by maltose- and glutathione-affinity column chromatography. Rabbit liver GST protein expressed by this system was catalytically active. The functional characterization was done on the expressed protein. The rabbit liver GST expressed in E. coli showed greater activity toward 1,2-dichloro-4-nitrobenzene than mu-class isozymes in rabbit hepatic tissue (T. Primiano and R.F. Novak (1993) Arch. Biochem. Biophys. 301, 404-410). Enzymatic activity of expressed protein toward the substrate 1-chloro-2,4-dinitrobenzene was inhibited by triethyltin bromide, Cibacron blue, triphenyltin chloride, bromosulfophthalein, and hematin. RNA blot hybridization demonstrated that the pHMB1 mRNA was well expressed in rabbit liver, brain, and kidney.
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PMID:Cloning and expression of a cDNA for mu-class glutathione S-transferase from rabbit liver. 773 73

Pulmonary diseases attributable to asbestos exposure constitute a significant public health burden, yet few studies have investigated potential genetic determinants of susceptibility to asbestos-related diseases. The glutathione-S-transferases are a family of conjugating enzymes that both catalyze the detoxification of a variety of potentially cytotoxic electrophilic agents and act in the generation of sulfadipeptide leukotriene inflammatory mediators. The gene encoding glutathione-S-transferase class mu (GSTM-1) is polymorphic; approximately 50% of Caucasian individuals have a homozygous deletion of this gene and do not produce functional enzyme. Glutathione-S-transferase mu (GST-mu) deficiency has been previously reported to be associated with smoking-induced lung cancer. We conducted a cross-sectional study to examine the prevalence of the homozygous deletion for the GSTM-1 gene in members of the carpentry trade occupationally exposed to asbestos. Members of the United Brotherhood of Carpenters and Joiners of America attending their 1991 National Union conference were invited to participate. Each participant was offered a chest X-ray and was asked to complete a comprehensive questionnaire and have their blood drawn. All radiographs were assessed for the presence of pneumoconiosis in a blinded fashion by a National Institute for Occupational Safety and Health-certified International Labor Office "B" reader. Individual GSTM-1 status was determined using polymerase chain reaction methods. Six hundred fifty-eight workers were studied. Of these, 80 (12.2%) had X-ray abnormalities associated with asbestos exposure. Individuals genetically deficient in GST-mu were significantly more likely to have radiographic evidence of nonmalignant asbestos-related disease than those who were not deficient (chi 2 = 5.0; P < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inherited glutathione-S-transferase deficiency is a risk factor for pulmonary asbestosis. 800 Feb 97


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