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)

Class mu glutathione S-transferases (GSTs) are important in the detoxication of epoxides generated by oxidative metabolism. Phenobarbital, 3-methylcholanthrene, and pyridine have failed to enhance the expression of class mu GST isozymes in rabbit hepatic tissue (T. Primiano, S. G. Kim, and R. F. Novak, Toxicol. Appl. Pharmacol., 113, 64-73, 1992). Two class mu GST isozymes have been isolated from rabbit hepatic cytosol and purified to homogeneity using S-hexylglutathione-agarose, CM-Sepharose, and PBE94 chromatofocusing chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analyses showed that both isozymes possessed M(r) values of approximately 25,500 and cross-reacted with class mu-specific GST IgG. Gel filtration analysis revealed that these isozymes were dimers with molecular weights of approximately 45 kDa. The class mu GST isozymes had pIs of 7.8 and 7.2 as determined by nonequilibrium pH gel electrophoresis. The class mu GST 7.8 and 7.2 isozymes exhibited different metabolic activities toward the substrates 1-chloro-2,4-dinitrobenzene, bromosulfophthalein, 1,2-epoxy-3-(p-nitrophenoxy)propane, trans-4-phenyl-3-buten-2-one, p-nitrobenzyl chloride, and 3,4-dichloronitrobenzene. Metabolic activity of the two GSTs toward the substrate 1-chloro-2,4-dinitrobenzene was inhibited by Cibacron blue, triethyltin bromide, S-hexylglutathione, bromosulfophthalein, and indomethacin. The amino acid composition of GST mu 7.8 and 7.2 was determined and found to be very similar to those of purified rat class mu GST isozymes. N-terminal analysis of the first 21 residues of the pI 7.8 class mu GST isozyme revealed that it had 71 and 81% sequence identity with the Yb1 and Yb2 subunits, respectively. Similarly, N-terminal analysis of the first 21 residues of the pI 7.2 class mu GST isozyme revealed a 75% sequence identity with either the rat Yb1 or Yb2 subunit. Examination of class mu GST expression in rabbit hepatic cytosol following treatment with a series of known inducers including phenobarbital, 3-methylcholanthrene, isosafrole, pyrazine, trans-stilbene oxide, butylated hydroxyanisole, and tert-butylhydroquinone was accomplished. The data show that these agents not only failed to enhance class mu GST expression, but that 3-methylcholanthrene and isosafrole caused suppression of class mu GSTs. These results provide evidence for the existence of two closely related class mu GST isozymes in rabbit hepatic tissue and suggest that the molecular mechanisms regulating GST expression differ between rat and rabbit in response to these xenobiotics.
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PMID:Purification and characterization of class mu glutathione S-transferase isozymes from rabbit hepatic tissue. 846 Sep 49

Cytosolic glutathione S-transferase (GST) activities toward 1-chloro-2,4-dinitro-benzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EA), 1,2-epoxy-3-(p-nitrophenoxyl)propane (EPNP), trans-4-phenyl-3-buten-2-one(t-PBO), delta 5-androstene-3,17-dione (ASD) and trans-stilbene oxide (t-SO); cytosolic glutathione peroxidase activity toward cumene hydroperoxide (CuOOH); and microsomal GST activity toward CDNB were examined in liver, kidney, brain, and lung of adult male and female Japanese quail. In all cases, the renal specific activity per milligram protein was higher than the hepatic activity and was the highest among the four tissues examined. No consistent sex differences in GST activity were observed. The GSTs were purified from quail liver cytosol by S-hexylglutathione and glutathione affinity chromatography. Total GSTs eluted from the S-hexylglutathione affinity column were further separated by chromatofocusing, and the microheterogeneity of the GST isozymes was shown by high-resolution native isoelectrofocusing (IEF) in polyacrylamide slab gels and by SDS-PAGE. Five subunits were identified: QL1 (30.5 kDa), QL2 (27.2 kDa), QL3a (26.8 kDa), QL3b (26.5 kDa), and QL4 (25.5 kDa). Western blot analysis revealed that QL1 and QL2 reacted with antibodies raised against the rat Mu class GSTs (Yb1 and Yb2), and QL3a and QL3b reacted with those raised against the Alpha class (rat Ya and mouse a). Substrate specific activity of each isoform was determined with CDNB, DCNB, CuOOH, EA, t-PBO, ASD, and t-SO. QL3a and QL3b have high reactivity toward CuOOH, while QL1 and QL2 showed high activity toward t-SO. The N-terminal amino acid sequence of QL2 was identical to that of the chicken Mu class GST subunit CL2. However, no sequence was obtained with QL1 due to possible N-terminal blockage.
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PMID:Glutathione S-transferases in the Japanese quail: tissue distribution and purification of the liver isozymes. 888 69

Glutathione S-transferase cGSTM1-1, an avian class-mu enzyme with high sequence identity with rGSTM3-3, was expressed heterologously in Escherichia coli. The three-dimensional structure of this protein that co-crystallized with an inhibitor, S-hexylglutathione, was determined by the molecular replacement method and refined to 1.94 A resolution. The three-dimensional structure and the folding topology of the dimeric cGSTM1-1 closely resembles those of other class-mu GSTs. The bound inhibitor, S-hexylglutathione, orients in disparate directions in the two subunits. The combined space occupied by the hexyl moiety of the inhibitors overlaps with that reported for rGSTM1-1 co-crystallized with (9 S,10 S)-9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene. Conformational differences at a flexible loop (residue 35 to 40) were also observed between the crystal structures of cGSTM1-1 and rGSTM1-1.cGSTM1-1 has the highest epoxidase activity among all the class-mu enzymes reported. Tyr115, has been identified as a residue that participates in the epoxidase activity of class-mu glutathione S-transferase and is conserved in cGSTM1-1. The epoxidase and trans-4-phenyl-3-buten-2-one conjugating activity of cGSTM1-1 are decreased drastically but not abolished by replacing Tyr115 with phenylalanine. The specificity constant of the cGSTM1-1(Y115F) mutant, with 1-chloro-2,4-dinitrobenzene as substrate, is 15-fold higher than that of the wild-type enzyme.
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PMID:The three-dimensional structure of an avian class-mu glutathione S-transferase, cGSTM1-1 at 1.94 A resolution. 957 Oct 47

We investigated the impact of glutathione transferases Mu 1 (GSTM1)- and glutathione transferase Theta 1 (GSTT1)-null genotypes on hepatic GST activities in humans and compared the results with those of Gstm1- and Gstt1-null mice. In liver with GSTM1/Gstm1-null genotype, GST activity toward p-nitrobenzyl chloride (NBC) was significantly decreased in both humans and mice. In addition, in liver with GSTT1/Gstt1-null genotype, GST activity toward dichloromethane (DCM) was significantly decreased in both humans and mice. Therefore, null genotypes of GSTM1/Gstm1 and GSTT1/Gstt1 are considered to decrease hepatic GST activities toward NBC and DCM, respectively, in both humans and mice. This observation shows the functional similarity between humans and mice for GSTM1 and GSTT1 toward some substrates. In the case of NBC and DCM, Gst-null mice would be relevant models for humans with GST-null genotype. In addition, decreases in GST activities toward 1,2-dichloro-4-nitrobenzene, trans-4-phenyl-3-buten-2-one, and 1-chloro-2,4,-dinitrobenzene were observed in Gstm1-null mice, and a decrease in GST activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was observed in Gstt1-null mice. However, an impact of GST-null genotypes on GST activities toward these substrates was not observed in humans. In the case of these mouse-specific substrates, Gst-null mice may be relevant models for humans regardless of GST genotype, because GST activities, which are higher in wild-type mice than in humans, were eliminated in Gst-null mice. This study shows that comparison of hepatic GST activities between humans and mice using genotype information would be valuable in using Gst-null mice as human models.
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PMID:Evaluation of hepatic glutathione transferase Mu 1 and Theta 1 activities in humans and mice using genotype information. 2217 Mar 31


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