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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 effect of hypophysectomy and subsequent treatment with adrenocorticotropic hormone (adrenocorticotropin, ACTH) on the isoenzymes of glutathione transferase in the rat adrenal gland was investigated. A large increase (approx. 11-fold) in the level of transferase subunit 4 was observed in hypophysectomized animals by immunoblotting. When the activity of glutathione transferase 4-4 was measured in adrenal cytosol using trans-stilbene oxide as a selective substrate, a 15-fold increase was noted. Lack of the pituitary hormone ACTH is apparently related to this increase, since treatment of hypophysectomized animals with ACTH for 2 weeks partially down-regulated subunit 4. Glutathione transferase subunits 3 and 8 in the adrenal were also increased in amount by hypophysectomy, but not at all to the same extent. The activity of glutathione transferase 4-4 was elevated also in the liver and ovary (5 and 1.5 times respectively) after hypophysectomy. These elevated enzyme levels were, however, not affected by ACTH treatment. This down-regulation of glutathione transferases in the rat adrenal by ACTH may be related to the fact that, under normal conditions, this organ is highly susceptible to the toxic effects of various polycyclic hydrocarbons, whereas under circumstances where there is no ACTH production, as in hypophysectomized rats, the adrenal is resistant to these same hydrocarbons.
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PMID:Increase in the amount of glutathione transferase 4-4 in the rat adrenal gland after hypophysectomy and down-regulation by subsequent treatment with adrenocorticotrophic hormone. 215 79

Under standard assay conditions, with 1-chloro-2,4-dinitrobenzene (CDNB) as electrophilic substrate, rat glutathione transferase 4-4 is strongly inhibited (I50 = 1 microM) by indomethacin. No other glutathione transferase investigated is significantly inhibited by micromolar concentrations of indomethacin. Paradoxically, the strong inhibition of glutathione transferase 4-4 was dependent on high (millimolar) concentrations of CDNB; at low concentrations of this substrate or with other substrates the effect of indomethacin on the enzyme was similar to the moderate inhibition noted for other glutathione transferases. In general, the inhibition of glutathione transferases can be explained by a random-order sequential mechanism, in which indomethacin acts as a competitive inhibitor with respect to the electrophilic substrate. In the specific case of glutathione transferase 4-4 with CDNB as substrate, indomethacin binds to enzyme-CDNB and enzyme-CDNB-GSH complexes with an even greater affinity than to the corresponding complexes lacking CDNB. Under presumed physiological conditions with low concentrations of electrophilic substrates, indomethacin is not specific for glutathione transferase 4-4 and may inhibit all forms of glutathione transferase.
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PMID:Paradoxical inhibition of rat glutathione transferase 4-4 by indomethacin explained by substrate-inhibitor-enzyme complexes in a random-order sequential mechanism. 339 Jan 38

IgG1 class mouse monoclonal antibodies (MAbs) were produced against human glutathione S-transferase Mu1-1 (GSTMu1-1). Eight MAbs of 16 are able to recognize only the native form of the enzyme; 4 MAbs bind to native and denaturated enzyme, and the remaining 4 can bind only to partially denatured antigen in direct ELISA or Western blot. The antibodies recognizing the native form of the enzyme bind to six different epitopes. Three overlapping epitopes are responsible for specific binding of MAbs to different allelic variants of GSTMu1-1. Three allele-specific antibodies, 2E1, 11F12, and 7D11, bind to GSTM1a monomer and the other two, 1H8 and 3H10, recognize GSTM1b monomer.
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PMID:Allele-specific monoclonal antibodies against glutathione S-transferase Mu1-1. 753 19

The Mu-Class glutathione S-transferases (GSTs) are subject to marked inter-individual variation in man, owing to the fact that 40-50% of the population fail to express M1 subunits. Mu-Class GST from two lymphoblastoid cell lines (expressing M1 subunits and the other 'nulled' for M1) have been studied. Both cell lines were found to express a Mu-Class GST that has not been described previously. The cDNA encoding this novel transferase, designated 'GSTM4' has been isolated and the enzyme shown to be comprised of 218 amino acids (including the initiator methionine residue) with an M(r) of approx. 25.5 kDa. Molecular cloning demonstrated that the lymphoblastoid cell line which expressed GSTM1 possessed the b allelic variant (i.e. that with an asparagine residue at position 173). The genes for GSTM4 and GSTM1b have been cloned and found to contain seven introns and eight exons. The coding region of the GSTM4 gene, including the seven introns, encompasses 5.0 kb, whereas the same region of GSTM1b is 5.5 kb; the difference in the size of the two genes is due to the length of intron 7. DNA sequencing allowed a GSTM4-gene-specific oligo-primer to be designed which has been utilized in a PCR-based assay to determine that the GSTM4 gene is located on chromosome 1.
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PMID:Deduced amino acid sequence, gene structure and chromosomal location of a novel human class Mu glutathione S-transferase, GSTM4. 847 Oct 52

An expression clone for large-scale production of the polymorphic human glutathione transferase (GST) M1-1 has been developed. Heterologous expression in Escherichia coli afforded a yield of 100 mg of GST M1-1 per 3 liters of culture medium, corresponding to an approximately 10-fold increased yield compared to the parental expression construct. Overproduction of the enzyme was dependent on the codon usage in the 5' region of the DNA sequence encoding glutathione transferase M1-1. High-level expression clones were generated by a combination of random silent mutations in selected wobble positions in the coding sequence and immunoselection of clones from the library of random mutants. The strategy used is generally applicable for the production of recombinant proteins provided that a suitable selection procedure is available for identifying the desired mutants.
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PMID:Optimized heterologous expression of the polymorphic human glutathione transferase M1-1 based on silent mutations in the corresponding cDNA. 877 53

In earlier experiments, adrenocorticotropic hormone (ACTH) was shown to decrease the level of glutathione transferase M1 (murine glutathione transferase mu-1) (mGSTM1), as well as of the corresponding mRNA, in a murine adrenocortical cell line. In the present study, the effect of ACTH on mGSTM1 gene transcription was examined using two techniques. First, a cDNA that coded for the mGSTM1 subunit but lacked the corresponding promoter sequences was transfected into the adrenocortical cell line, and the effect of ACTH on the level of the corresponding transcript was compared to that of endogenous mGSTM1 mRNA. The other technique used was nuclear run-on transcription, where the rate of transcription of endogenous mGSTM1 mRNA in ACTH-treated cells was compared to that in untreated control cells. These experimental approaches indicated that the rate of transcription of the mGSTM1 gene is regulated by ACTH in adrenocortical cells.
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PMID:Regulation of the GST Mu-1 isoenzyme in Y1 cells by adrenocorticotropic hormone is primarily transcriptional. 1142 22

Glutathione S-transferases (GSTs) catalyze the conjugation of glutathione to numerous potentially genotoxic compounds. The GSTM1 gene codes for the enzyme glutathione S-transferase-mu, the GSTT1 gene codes for the enzyme glutathione S-transferase-theta, and the GSTP1 gene codes for the enzyme glutathione S-transferase-pi. GSTM1 is polymorphically expressed, and three alleles have been identified (GSTM1-0, GSTM1a, and GSTM1b). Two functionally different genotypes at the GSTT1 locus have been described. Individuals with homozygous deletions of GSTM or GSTT have reduced or no glutathione S-transferase activity and therefore may be unable to eliminate electrophilic carcinogens as efficiently. However, results of epidemiologic studies do not confirm associations between GSTM1, GSTT1, and GSTP1 and epithelial ovarian cancer.
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PMID:Glutathione S-transferase polymorphisms and risk of ovarian cancer: a HuGE review. 1217 91

The objective of this study was to identify cellular and plasma marker(s) of post-I/R (ischaemia/reperfusion) in patients undergoing elective knee surgery where a tourniquet was used to facilitate a bloodless surgical field. We evaluated the inflammatory and redox response by measuring the mRNA levels of ICAM-1 (intercellular cell-adhesion molecule-1), MnSOD (manganese superoxide dismutase), GST-mu (glutathione transferase-mu) and Cu/ZnSOD (copper/zinc superoxide dismutase) in the operated muscle and blood cells pre-operatively (pre-tourniquet) and at various times after reperfusion (tourniquet release). We also measured plasma concentrations of IL (interleukin)-6, IL-8, sICAM-1 (soluble ICAM-1), IL-1beta and TNF-alpha (tumour necrosis factor-alpha) using ELISA. Our results show a strong induction of MnSOD and GST-mu in granulocytes (but not in mononuclear cells or muscle) after reperfusion (2 and 4 h). There was no change in the mRNA level of Cu/ZnSOD after reperfusion. An up-regulation of membrane ICAM-1 in muscle and a decrease in sICAM-1 in plasma were detected after reperfusion. Plasma IL-6 and IL-8 levels (but not TNF-alpha or IL-1beta) increased significantly over baseline at 2 and 4 h after reperfusion. Elevated expression of ICAM-1 in muscle, MnSOD and GST-mu in granulocytes and increased levels of plasma IL-6 and IL-8 may be considered as phase- and cell-specific markers of post-I/R of skeletal muscle in humans.
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PMID:Inflammatory and redox responses to ischaemia/reperfusion in human skeletal muscle. 1528 98

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) is an important component in the stress-activated protein kinase pathway. Glutathione S-transferase Mu 1-1 (GST M1-1) has now been shown to inhibit the stimulation of MEKK1 activity induced by cellular stresses such as UV and hydrogen peroxide. GST M1-1 inhibited MEKK1 activation in a manner independent of its glutathione-conjugating catalytic activity. In vitro binding and kinase assays revealed that GST M1-1 directly bound MEKK1 and inhibited its kinase activity. Co-immunoprecipitation analysis showed a physical association between endogenous GST M1-1 and endogenous MEKK1 in L929 cells. Overexpressed GST M1-1 interfered with the binding of MEKK1 to SEK1 in transfected HEK293 cells. Furthermore, GST M1-1 suppressed MEKK1-mediated apoptosis. Taken together, our results suggest that GST M1-1 functions as a negative regulator of MEKK1.
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PMID:Negative regulation of MEKK1-induced signaling by glutathione S-transferase Mu. 1529 5

Although rat glutathione transferase M1-1 is crystallized as a homodimer (GST M1-1), we have generated monomers (GST M1) of the enzyme by adding potassium bromide to buffer solutions containing the wild-type enzyme and by introducing point mutations in the electrostatic region of the subunit interface. The wild-type enzyme was evaluated in 0.05 M MES (pH 6.5) containing up to 3 M KBr. We report that the addition of KBr greatly influences the monomer-dimer equilibrium of the wild-type enzyme and that at 3 M KBr GST M1 has a specific activity close to that of GST M1-1. Since the effect of KBr is likely due to charge screening at the subunit interface, the influence on the monomer-dimer equilibrium exerted by the amino acid residues in the electrostatic region of the interface (Arg77, Asp97, Glu100, Asn101) was investigated. Mutations introduced at positions 97, 100, and 101 promote monomerization, resulting in enzymes that exhibit a decreased weight average molecular weight in comparison to that of the wild-type enzyme. However, only mutations at position 97 result in enzymes that have catalytic activity in the monomeric form. The mutations introduced at positions 100 or 101 result in enzymes whose activity can be accounted for by the amount of dimeric enzyme present. Our results indicate that the electrostatic region of the interface is important in the monomer-dimer equilibrium of glutathione transferase and that, although GST M1-1 may be more active than GST M1, the dimer is not required for catalytic function.
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PMID:Catalytically active monomer of class mu glutathione transferase from rat. 1668 69


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