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)

We have reported previously that a dietary deficiency in selenium results in an increase in glutathione S-transferase (GST) activity of various rat tissues. In order to verify that the increased GST activity observed in a selenium deficiency results from increased synthesis of GST protein, cytosolic fractions of livers obtained from rats fed selenium-deficient and selenium-supplemented diets were analyzed by Western (protein) blots. Antisera raised against purified individual GST subunits (Ya, Yb, and Yc) were used to detect the corresponding subunits on the blots. The Ya subunit was induced 2.5-fold in the selenium-deficient state. The amount of Yc subunit also increased significantly (p less than 0.05) in selenium deficiency but not to the extent of the Ya subunit. The Yb subunit was not significantly affected by altered selenium nutritional status. A corresponding increase in poly(A) RNAs coding for the Ya and Yc subunits was also observed by Northern blot analysis. Transcriptional activity of GST YaYc genes was elevated by approximately 2-fold in purified nuclei isolated from selenium-deficient rat livers, which is sufficient to account for the increase in YaYc mRNA levels. Therefore, it appears that transcriptional activation of rat liver YaYc genes is the primary cause for the elevation of the corresponding gene products in the selenium-deficient state. Since the GSTs, especially the isozymes containing Ya subunit, have been implicated in the formation of prostaglandin (PG) F2 alpha, we investigated the effect of selenium deficiency on the PGF2 alpha-forming activity using a specific inhibitor of GSTs, S-decyl-GSH. In rats fed a nutritionally adequate diet, the activity inhibited by S-decyl-GSH accounted for at least half of the conversion of PGH2 to PGF2 alpha. During selenium deficiency, this GST-catalyzed activity was approximately doubled with no change in PGF2 alpha formation by other pathways, resulting in a 2-fold increase in overall synthesis of PGF2 alpha. These data strongly support a role of GSTs, especially those composed of the Ya size subunit, in the synthesis of PGF2 alpha from PGH2.
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PMID:The induction of specific rat liver glutathione S-transferase subunits under inadequate selenium nutrition causes an increase in prostaglandin F2 alpha formation. 169 Jul 9

In recent years, growing evidence suggests that glutathione peroxidases (GSH-Pxs), both selenium-dependent GSH-Px (Se-GSH-Px) and selenium-independent GSH-Px (non-Se-GSH-Px) play an important role in the biosynthesis of prostaglandins and leukotrienes and in the regulation of key enzymes associated with the arachidonic acid cascade. The precise nature of their involvement in eicosanoid metabolism, however, is not yet completely understood. In the study reported here, we have systematically determined the catalytic efficiencies of Se-GSH-Px and non-Se-GSH-Px toward prostaglandin (PG) G2 (PGG2) and PGH2. Se-GSH-Px exhibited high catalytic activity for the reduction of PGG2 as indicated by Km and Vmax values of 12 microM and 78 mumol/min/mg, respectively, whereas PGH2 was found to be a poor substrate, an indication that Se-GSH-Px reduces the hydroperoxide moiety but not the endoperoxide moiety of PGG2. The kinetic constants of Se-GSH-Px toward PGG2 were comparable to those determined for such classical substrates as H2O2 and cumene hydroperoxide. In contrast to Se-GSH-Px, non-Se-GSH-Px associated with cationic isozyme II of glutathione S-transferases (GSTs) from sheep lung cytosol was very active in the conversion of PGH2 to PGF2 alpha with a Vmax of 960 nmol/min/mg and a Km of 77 microM. This study shows that PGF2 alpha formation by non-Se-GSH-Px occurred in a GSH-dependent reduction of either PGG2 or PGH2. When PGG2 was used as the substrate for non-Se-GSH-Px, a novel intermediate compound appeared and was later identified by several methods of structural analysis as 15-hydroperoxy PGF2 alpha. Thus, the reductive cleavage of the endoperoxide occurs faster than the 15-hydroperoxide reduction allowing 15-hydroperoxy PGF2 alpha to accumulate briefly. A study of GSTs from several different tissues and species indicated that the transformation of PG endoperoxides to PGF2 alpha is catalyzed specifically by GST isozymes, which contain Ya size subunits. This specificity of GST isozymes in PG biosynthesis, coupled with their tissue-specific expression, may be a mechanism by which the body modulates the type of PGs produced in these tissues. Also, these results suggest a possible interaction of Se-GSH-Px and non-Se-GSH-Px in the biosynthesis of PGF2 alpha.
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PMID:The role of selenium-dependent and selenium-independent glutathione peroxidases in the formation of prostaglandin F2 alpha. 276 44

Hematopoietic prostaglandin (PG) D synthase is the key enzyme for production of the D and J series of prostanoids in the immune system and mast cells. We isolated a cDNA for the rat enzyme, crystallized the recombinant enzyme, and determined the three-dimensional structure of the enzyme complexed with glutathione at 2.3 A resolution. The enzyme is the first member of the sigma class glutathione S-transferase (GST) from vertebrates and possesses a prominent cleft as the active site, which is never seen among other members of the GST family. The unique 3-D architecture of the cleft leads to the putative substrate binding mode and its catalytic mechanism, responsible for the specific isomerization from PGH2 to PGD2.
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PMID:Cloning and crystal structure of hematopoietic prostaglandin D synthase. 932 36

Prostaglandin (PG) D synthase catalyzes the isomerization of PGH2, a common precursor of various prostanoids, to produce PGD2 in the presence of sulfhydryl compounds. PGD2 induces sleep, regulates nociception, inhibits platelet aggregation, acts as an allergic mediator, and is further converted to 9 alpha, 11 beta-PGF2 or the J series of prostanoids, such as PGJ2, delta 12-PGJ2, and 15-deoxy-delta 12,14-PGJ2. We have purified two distinct types of PGD synthase; one is the lipocalin-type enzyme and the other is the hematopoietic enzyme. We isolated the cDNA and the gene for each enzyme and determined the tissue distribution profile and the cellular localization in several animal species. Lipocalin-type PGD synthase is localized in the central nervous system and male genital organs of various mammals and the human heart and is secreted into cerebrospinal fluid, seminal plasma, and plasma, respectively. The human enzyme was identified as beta-trace, which is a major protein in human cerebrospinal fluid. This enzyme is considered to be a dual-function protein; it acts as a PGD2-producing enzyme and also as a lipophilic ligand-binding protein, because the enzyme binds retinoids, thyroids, and bile pigments, with high affinities. Hematopoietic PGD synthase is widely distributed in the peripheral tissues and localized in the antigen-presenting cells, mast cells, and megakaryocytes. The hematopoietic enzyme is the first recognized vertebrate homolog of the sigma class of glutathione S-transferase. X-ray crystallographic analyses and generation of gene-knockout and transgenic mice for each enzyme have been performed.
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PMID:Prostaglandin D synthase: structure and function. 1066 96

Cytosolic prostaglandin (PG) E synthase was purified from human brain cortex. The N-terminal amino acid sequence, PMTLGYXNIRGL, was identical to that of the human mu-class glutathione transferase (GST) M2 subunit. Complementary DNAs for human GSTM2, GSTM3, and GSTM4 subunits were cloned, and recombinant proteins were expressed as homodimers in Escherichia coli. The recombinant GSTM2-2 and 3-3 catalyzed the conversion of PGH2 to PGE2 at the rates of 282 and 923 nmol/min/mg of protein, respectively, at the optimal pH of 8, whereas GSTM4-4 was inactive; although all three enzymes showed GST activity. The PGE synthase activity depended on thiols, such as glutathione, dithiothreitol, 2-mercaptoethanol, or L-cysteine. Michaelis-Menten constants and turnover numbers for PGH2 were 141 microM and 10.8 min(-1) for GSTM2-2 and 1.5 mM and 130 min(-1) for GSTM3-3, respectively. GSTM2-2 and 3-3 may play crucial roles in temperature regulation, nociception, and sleep-wake regulation by producing PGE2 in the brain.
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PMID:Identification of mu-class glutathione transferases M2-2 and M3-3 as cytosolic prostaglandin E synthases in the human brain. 1090 36

The role of transforming growth factor alpha (TGFalpha) and prostaglandins (PGs) in the preferential growth of preneoplastic liver cells was studied. Rats received the genotoxic hepatocarcinogen N-nitrosomorpholine (NNM); placental glutathione S-transferase (GSTp) was used as a marker to identify preneoplastic foci. Preneoplastic foci expressing TGFalpha (TGFalpha(+)) grew more rapidly than TGFalpha negative (TGFalpha(-)) ones. Almost all tumours studied were positive for TGFalpha. The key enzymes of prostaglandin synthesis, cyclooxygenase I (Cox-1) and II (Cox-2), were present in all unaltered and preneoplastic cells and tended to decrease in the later stages of hepatocarcinogenesis. Immunostaining revealed that cultures of hepatocytes, isolated from NNM-treated livers by collagenase perfusion, contained 1-2% GSTp-positive (GSTp(+)) and 9% TGFalpha(+) hepatocytes; 0.6% of the cells were GSTp(+)/TGFalpha(+). Cox-1 and Cox-2 were present in all cells. DNA replication was almost exclusively associated with expression of TGFalpha. GSTp(+) hepatocytes showed a 3- to 4-fold higher probability of TGFalpha expression and of DNA synthesis than GSTp-negative (GSTp(-)) cells. PGE(2) or PGF(2alpha) increased expression of TGFalpha and DNA replication in GSTp(-) cells but not in GSTp(+) cells. PGA(2) and PGJ(2) decreased DNA synthesis in TGFalpha(+) cells without an obvious effect on the intracellular levels of TGFalpha. The Cox-2 inhibitor SC236 suppressed DNA replication preferentially in GSTp(+) cells; this inhibition was reversed by PGE(2)/F(2alpha). Indomethacin had no effect. These results suggest the following conclusions. (i) Growth regulation of preneoplastic GSTp(+) cells in culture exhibits distinct differences from GSTp(-) cells and elevated expression of TGFalpha contributes to their growth advantage. (ii) TGFalpha renders preneoplastic hepatocytes sensitive to suppression of DNA synthesis by PGA(2)/J(2). (iii) SC236, a Cox-2 inhibitor, may have preventive value in hepatocarcinogenesis.
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PMID:Role of transforming growth factor alpha and prostaglandins in preferential growth of preneoplastic rat hepatocytes. 1147 Jul 56

Prostaglandin E synthase (PGES), which converts cyclooxygenase (COX)-derived prostaglandin (PG)H2 to PGE2, occurs in multiple forms with distinct enzymatic properties, modes of expression, cellular and subcellular localizations and intracellular functions. Cytosolic PGES (cPGES) is a cytosolic protein that is constitutively expressed in a wide variety of cells and tissues and is associated with heat shock protein 90 (Hsp90). Membrane-associated PGES (mPGES), the expression of which is stimulus-inducible and is downregulated by anti-inflammatory glucocorticoids, is a perinuclear protein belonging to the microsomal glutathione S-transferase (GST) family. These two PGESs display distinct functional coupling with upstream COXs in cells; cPGES is predominantly coupled with the constitutive COX-1, whereas mPGES is preferentially linked with the inducible COX-2. Several cytosolic GSTs also have the capacity to convert PGH2 to PGE2 in vitro. Accumulating evidence has suggested that mPGES participates in various pathophysiological states in which COX-2 is involved, implying that mPGES represents a potential novel target for drug development.
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PMID:Prostaglandin E synthase. 1243 31

Recombinant human microsomal prostaglandin E(2) synthase-1 (mPGES-1) was expressed in a baculovirus-Sf9 cell system. The mPGES-1 was solubilized from Sf9 cell membranes with diheptanoylphosphatidylcholine and purified in the presence of octylglucoside using hydroxyapatite column chromatography. The K(m) values of the substrates PGH(2) and GSH were 14 microM and 0.75 mM, respectively, with the purified enzyme. The specific activity (4 micromol/min/mg) was increased 3-5-fold by non-ionic and zwitterionic detergents. Kinetic analysis showed that dodecylmaltoside increases V(max) but does not affect the K(m) values of either substrate. Several other thiol-containing compounds were tested as glutathione replacements, none of which yielded detectable enzyme activity. During enzyme catalysis, glutathione was not oxidized and therefore can be considered an enzyme cofactor. No glutathione transferase or peroxidase activity could be determined with a range of potential substrates. The results show that purified mPGES-1 has a specific activity similar to Cox-2, consistent with its postulated role in Cox-2 mediated PGE(2) formation.
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PMID:Purification and characterization of recombinant microsomal prostaglandin E synthase-1. 1246 Jul 74

Polychlorinated biphenyls (PCBs) have been shown to be embryotoxic. The mechanism(s) of action is not clearly understood. The toxic effects could be either direct or indirect. Furthermore, PCB congeners vary in their toxic potential. They can be classified in coplanar PCBs binding to the transcription factor aryl hydrocarbon receptor (AhR), which induce subsequent changes in gene expression, and noncoplanar PCBs exhibiting AhR-independent effects. In order to investigate possible mechanisms, 5 and 6 days old preimplantation rabbit embryos were exposed in vitro to low levels of coplanar (PCB 77, 126, and 169) or noncoplanar PCBs (PCB 28, 52, 101, 118, 138, 153, and 180). The PCB effects were studied by semiquantitative RT-PCR analysis of AhR target genes (cytochrome P450 (CYP) 1A1, 1A2, UDP-glucuronosyl transferase 1, glutathione S-transferase pi1 and aldehyde dehydrogenase) and dioxin-responsive genes (IL 1beta, PAI 2, Cox 2, TGFalpha, EGF, erbB 1-4, c-fos, c-jun, HSP 90, cyclophilin 40), and by differential display (DD) RT-PCR. CYP 1B1 mRNA and AhR protein were localized by in situ hybridization and immunohistochemistry, respectively. From the AhR target genes studied only CYP 1B1, and cyclooxygenase 2 showed an increase in mRNA levels after coplanar and noncoplanar PCB. Interleukin 1beta and plasminogen activator inhibitor 2 were downregulated. CYP 1B1 mRNA showed a stage specific inducibility at day 6, but not at day 5. By DD RT-PCR we identified six new genes previously not reported to be regulated by PCBs. The mRNAs encoding the subunits 1, 2, 4, and 5 of the NADH ubiquinone oxidoreductase and beta-globin showed a decrease, whereas trichohyalin mRNA was increased after PCB exposure. Coplanar and noncoplanar PCB congeners elicited similar responses on the mRNA levels of the studied genes. Exposure to coplanar PCBs did not result in the AhR being translocated to the nucleus. Our results show that (i). PCBs induce changes in gene expression in rabbit day 5 and 6 preimplantation embryos and imply (ii). that the transcriptional changes observed were not mediated by the nuclear AhR.
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PMID:Polychlorinated biphenyls affect gene expression in the rabbit preimplantation embryo. 1254 57

Dihydrodiol dehydrogenase (DDH) is one of the major enzymes catabolizing polycyclic aromatic hydrocarbons in the liver. Although four DDH isoforms have been detected in the normal liver, only DDH1 and DDH2 have been detected in cancer cells of lung and esophagus. Moreover, the available information about hepatic pathophysiological regulation of DDH expression is limited. Therefore we addressed the question of DDH expression in patients with liver disorders, in particular, patients with hepatocellular carcinoma (HCC). Expression of DDH1/2 was determined by immunohistochemistry, immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR) in 52 patients with resected HCC. DDH1/2 expression was detected in 31 (59.6%) of 52 pathological sections. Frequency of DDH1/2 expression was significantly higher in patients with tumor size >2 cm, and in those who had early local recurrence. In addition to the tumor size and frequency of local recurrence, our results further indicated that expression of DDH1/2 was correlated with those of cyclooxygenase 2 (COX-2), interleukin-6 (IL-6), microsomal epoxide hydrolase (mEpH) and soluble epoxide hydrolase (sEpH) in HCC patients. Interestingly, the expression of DDH1/2 was found inversely correlated with that of glutathione S-transferase (GST) and NADPH p450 reductase (NPR). In conclusion, these results indicate that DDH expression was significantly decreased in about 40% of HCC patients. However, in the bordering non-neoplastic region of liver DDH1/2 expression increased, and the increased DDH1/2 expression correlated with tumor size and the disease progression.
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PMID:Reduction of dihydrodiol dehydrogenase expression in resected hepatocellular carcinoma. 1257 57


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