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

---

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 genetic polymorphisms for glutathione S-transferase ( GST) M1, GSTT1, GSTP1-1( GSTP1), cytochrome P450 2E1 ( CYP2E1) and aldehyde dehydrogenase 2 ( ALDH2) on the risk of hepatocellular carcinoma (HCC) was observed in 78 Japanese patients with HCC and 138 non-cancer hospital controls. We found a positive association between cumulative amounts of alcohol consumption (>/=600,000 ml in a lifetime) and the risk of HCC (OR=4.52, 95% CI 2.39-8.55). However, cigarette smoking was not significantly related to the risk of HCC (OR=1.23, 95% CI 0.57-2.68). The allelic frequencies of GSTM1, GSTT1, GSTP1, CYP2E1and ALDH2of HCC patients were not significantly different from those of controls when odds ratios were only adjusted for age and gender except for any 2 alleles of ALDH2in drinkers (OR=2.53, 95% CI 1.21-5.31). However, the frequency of any C2 alleles of CYP2E1and any 2 alleles of ALDH2were significantly higher than those of controls (OR=5.77, 95% CI 1.24-27.39, OR=9.77, 95% CI 1.63-58.60) when covariates including viremia were selected by using stepwise logistic regression analysis. We conclude that habitual alcohol drinking is likely to lead to an increased risk of HCC, and any C2alleles of CYP2E1as well as any two alleles of ALDH2were also associated with an increased risk of HCC.
...
PMID:Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. 1275 47

In addition to glutathione (GSH) conjugating activity, glutathione S-transferases (GSTs) catalyze "reverse" reactions, such as the hydrolysis of GSH thiol esters. Reverse reactions are of interest as potential tumor-directed pro-drug activation strategies and as mechanisms for tissue redistribution of carboxylate-containing drugs. However, the mechanism and specificity of GST-mediated GSH thiol ester hydrolysis are uncharacterized. Here, the GSH thiol esters of ethacrynic acid (E-SG) and several nonsteroidal antiinflammatory agents have been tested as substrates with human GSTs. The catalytic hydrolysis of these thiol esters appears to be a general property of GSTs. The hydrolysis of the thiol ester of E-SG was studied further with GSTA1-1 and GSTP1-1, as a model pro-drug with several possible fates for the hydrolysis products: competitive inhibition, covalent enzyme adduction, and sequential metabolism. In contrast to hydrolysis rates, significant isoform-dependent differences in the subsequent fate of the products ethacrynic acid and GSH were observed. At low [E-SG], only the GSTP1-1 efficiently catalyzed sequential metabolism, via a dissociative mechanism.
...
PMID:Exploration of in vitro pro-drug activation and futile cycling by glutathione S-transferases: thiol ester hydrolysis and inhibitor maturation. 1278 83

Electron paramagnetic resonance and kinetics experiments have been made to determine the formation, stability, and fate of the natural nitric oxide carrier, dinitrosyl-diglutathionyl-iron complex (DNDGIC), in heterogeneous systems approaching in vivo conditions. Both in human placenta and rat liver homogenates DNDGIC is formed spontaneously from GSH, S-nitroso-glutathione, and trace amounts of ferrous ions. DNDGIC is unstable in homogenates depleted of glutathione S-transferase (GST); an initial phase of rapid decomposition is followed by a slower decay, which is inversely proportional to the concentration. In the crude human placenta homogenate, GSTP1-1, which represents 90% of the cytosolic GST isoenzymes, is the preferential target for DNDGIC. It binds the complex almost stoichiometrically and stabilizes it for several hours (t1/2 = 8 h). In the presence of an excess of DNDGIC, negative cooperativity in GSTP1-1 opposes the complete loss of the usual detoxicating activity of this enzyme. In the rat liver homogenate, multiple endogenous GSTs (mainly Alpha and Mu class isoenzymes) bind the complex quantitatively and stabilize it (t1/2 = 4.5 h); negative cooperativity is also seen for these GSTs. Thus, the entire pool of cytosolic GSTs, with the exception of the Theta GST, represents a target for stoichiometric amounts of DNDGIC and may act as storage proteins for nitric oxide. These results confirm the existence of a cross-link between NO metabolism and the GST superfamily.
...
PMID:Glutathione transferase superfamily behaves like storage proteins for dinitrosyl-diglutathionyl-iron complex in heterogeneous systems. 1287 31

The interaction of dinitrosyl-diglutathionyl-iron complex (DNDGIC), a natural carrier of nitric oxide, with representative members of the human glutathione transferase (GST) superfamily, i.e. GSTA1-1, GSTM2-2, GSTP1-1, and GSTT2-2, has been investigated by means of pre-steady and steady state kinetics, fluorometry, electron paramagnetic resonance, and radiometric experiments. This complex binds with extraordinary affinity to the active site of all these dimeric enzymes; GSTA1-1 shows the strongest interaction (KD congruent with 10-10 m), whereas GSTM2-2 and GSTP1-1 display similar and slightly lower affinities (KD congruent with 10-9 m). Binding of the complex to GSTA1-1 triggers structural intersubunit communication, which lowers the affinity for DNDGIC in the vacant subunit and also causes a drastic loss of enzyme activity. Negative cooperativity is also found in GSTM2-2 and GSTP1-1, but it does not affect the catalytic competence of the second subunit. Stopped-flow and fluorescence data fit well to a common minimal binding mechanism, which includes an initial interaction with GSH and a slower bimolecular interaction of DNDGIC with one high and one low affinity binding site. Interestingly, the Theta class GSTT2-2, close to the ancestral precursor of GSTs, shows very slow binding kinetics and hundred times lowered affinity (KD congruent with 10-7 m), whereas the bacterial GSTB1-1 is not inhibited by DNDGIC. Molecular modeling and EPR data reveal structural details that may explain the observed kinetic data. The optimized interaction with this NO carrier, developed in the more recently evolved GSTs, may be related to the acquired capacity to utilize NO as a signal messenger.
...
PMID:The specific interaction of dinitrosyl-diglutathionyl-iron complex, a natural NO carrier, with the glutathione transferase superfamily: suggestion for an evolutionary pressure in the direction of the storage of nitric oxide. 1287 45

The organo(thio)phosphate esters are one of the most widely used classes of insecticides. Worldwide, organophosphate insecticides (OPs) result in numerous poisonings each year. In insects, glutathione S-transferases (GSTs) play an important role in OP resistance; limited data suggest that GST-mediated O-dealkylation occurs in humans as well. To characterize the capacity of mammalian GSTs to detoxify OPs, we investigated mammalian GST biotransformation of the widely used OP, methyl parathion (MeP). Cytosolic fractions isolated from rat, mouse, and ten individual adult human livers biotransformed 300 microM MeP at rates of 2.36, 1.76, and 0.70 (mean rate) nmol desmethyl parathion/min/mg, respectively. Our study focused on human GSTs; in particular, we investigated hGSTs M1-1 and T1-1, since deletion polymorphisms occur commonly in these genes. However, we found no correlation between hGSTM1/T1 genotypes and MeP O-dealkylation activities of the ten human liver cytosolic samples. We also measured MeP O-dealkylation activities of several purified recombinant GSTs belonging to the alpha (human GSTs A1-1 and A2-2, mouse GSTA3-3, rat GSTA5-5), mu (human GSTs M1a-1a, M2-2, M3-3, M4-4), pi (human GSTP1-1, mouse GSTs P1-1, P2-2), and theta (human GSTT1-1) classes. At 1 mM glutathione and 300 microM MeP concentrations, hGSTT1-1 and hGSTA1-1 exhibited the highest O-dealkylation activities: 545.8 and 65.0 nmol/min/mg, respectively. When expression level and enzymatic activity are considered, we estimate that hGSTA1-1 is responsible for the majority of MeP O-dealkylation in human hepatic cytosol. In target organs such as brain and skeletal muscle, where hGSTT1-1 is expressed, hGSTT1-1-mediated biotransformation of MeP may be important.
...
PMID:Biotransformation of methyl parathion by glutathione S-transferases. 1510 50

Atrazine is one of the most widely used herbicides in the United States and has been detected, occasionally, at low levels in drinking water sources. The biotransformation of atrazine in humans has not been fully characterized. Rodent studies suggest Phase I-dominated biotransformation with minor Phase II-mediated biotransformation by glutathione S-transferase(s) (GST). In human urine, mercapturates of atrazine are significant metabolites, yet the specific GST form(s) responsible for glutathione (GSH) conjugation have not been identified. Using recombinant alpha, mu, pi and theta class human GSTs, we demonstrated that only hGSTP1-1 displays significant activity toward atrazine (7.1 nmol/min/mg protein). We also confirmed that mouse GST Pi (pi) protein is responsible for the GSH-dependent biotransformation of atrazine in mouse liver; recombinant mGSTP1-1 had a specific activity of 7.3-nmol/min/mg protein. Furthermore, cytosolic fractions from mouse and human liver conjugated atrazine with glutathione at rates of 282.3 and 3.0 pmol/min/mg, respectively. Docking studies of the atrazine-GST conjugate in the hGSTP1-1 substrate-binding site were used to elucidate a basis for the dramatic difference in activity between mouse GSTP1-1 and GSTP2-2 (7.14 versus 0.02 nmol/min/mg protein, respectively). The inactivity of mGSTP2-2 appears to be attributable to an indirect structural disruption of the G-site by Pro12. Possible effects of the hGSTP1 polymorphisms were investigated. No significant differences in catalytic-specific activity were noted among purified proteins corresponding to the four hGSTP1 variants: hGSTP1(*)A (most common form), hGSTP1(*)B (Ile105Val), hGSTP1(*)C (Ile105Val, Ala114Val), and hGSTP1(*)D (Ala114Val). Overall, this work supports a physiological role for GSTs in atrazine biotransformation and indicates a novel diagnostic substrate for human and mouse GSTP1-1 proteins.
...
PMID:Characterization of atrazine biotransformation by human and murine glutathione S-transferases. 1511 87

In addition to their catalytic functions, GSTs (glutathione S-transferases) bind a wide variety of structurally diverse non-substrate ligands. This ligandin function is known to result in the inhibition of catalytic function. The interaction between hGSTA1-1 (human class Alpha GST with two type 1 subunits) and a non-substrate anionic ligand, BSP (bromosulphophthalein), was studied by isothermal titration calorimetry and inhibition kinetics. The binding isotherm is biphasic, best described by a set of two independent sites: a high-affinity site and a low-affinity site(s). The binding stoichiometries for these sites are 1 and 3 molecules of BSP respectively. BSP binds to the high-affinity site 80 times more tightly (K(d)=0.12 microM) than it does to the low-affinity site(s) (K(d)=9.1 microM). Binding at these sites is enthalpically and entropically favourable, with no linkage to protonation events. Temperature- and salt-dependent studies indicate the significance of hydrophobic interactions in the binding of BSP, and that the low-affinity site(s) displays low specificity towards the anion. Binding of BSP results in the release of ordered water molecules at these hydrophobic sites, which more than offsets unfavourable entropic changes during binding. BSP inhibition studies show that the binding of BSP to its high-affinity site does not inhibit hGSTA1-1. This site, located near Trp-20, may be related to the buffer-binding site observed in GSTP1-1. The low-affinity-binding site(s) for BSP is most probably located at or near the active site of hGSTA1-1. Binding to this site(s) results in non-competitive inhibition with respect to CDNB (1-chloro-2,4-dinitrobenzene) (K(i)(BSP)=16.8+/-1.9 microM). Given the properties of the H site and the relatively small size of the electrophilic substrate CDNB, it is plausible that the active site of the enzyme can simultaneously accommodate both BSP and CDNB. This would explain the non-competitive behaviour of certain inhibitors that bind the active site (e.g. BSP).
...
PMID:Characterization of bromosulphophthalein binding to human glutathione S-transferase A1-1: thermodynamics and inhibition kinetics. 1514 39

The Zeta class of glutathione transferases (GSTs) has only recently been discovered and hence has been poorly characterized. Here we investigate the substrate binding and kinetic mechanisms of the human Zeta class GSTZ1c-1c by means of pre-steady state and steady-state experiments and site-directed mutagenesis. Binding of GSH occurs at a very low rate compared with that observed for the more recently evolved GSTs (Alpha, Mu, and Pi classes). Moreover, the single step binding mechanism observed in this enzyme is reminiscent of that found for the Theta class enzyme, whereas the Alpha, Mu, and Pi classes have adopted a multistep binding mechanism. Replacement of Cys16 with Ala increases the rate of GSH release from the active site causing a 10-fold decrease of affinity toward GSH. Cys16 also plays a crucial role in co-substrate binding; the mutant enzyme is unable to bind the carcinogenic substrate dichloroacetic acid in the absence of GSH. However, both substrate binding and GSH activation are not rate-limiting in catalysis. A peculiarity of the hGSTZ1c-1c is the half-site activation of bound GSH. This suggests a primitive monomer-monomer interaction that, in the recently diverged GSTP1-1, gives rise to a sophisticated cooperative mechanism that preserves the catalytic efficiency of this GST under stress conditions.
...
PMID:Binding and kinetic mechanisms of the Zeta class glutathione transferase. 1517 70

The glutathione (GSH)/glutathione S-transferase (GST) system is an important detoxification system in the gastrointestinal tract. A high activity of this system may benefit cancer prevention. The aim of the study was to assess whether habitual consumption of fruits and vegetables, especially citrus fruits and brassica and allium vegetables, is positively associated with parameters reflecting the activity of the GSH/GST enzyme system in human rectal mucosa. GST enzyme activity, GST isoenzyme levels of GST-alpha (A1-1, A1-2 and A2-2), -mu (M1-1) and -pi (P1-1), and GSH levels were measured in rectal biopsies from 94 subjects. Diet, lifestyle, GSTM1 and GSTT1 null polymorphisms were assessed. Mean GST enzyme activity was 237 nmol/min/mg protein (SD = 79). Consumption of citrus fruits was positively associated with GST enzyme activity [difference between high and low consumption: 28.9 (95% confidence interval (CI) = 9.3-48.6) nmol/min/mg protein], but was not associated with the other parameters. A positive association with brassica vegetables was found among carriers of the GSTM1-plus genotype [difference between high and low consumption: 22.6 (95% CI = 0.2-45.0) nmol/min/mg protein], but not among GSTM1-null individuals (-25.8 nmol/min/mg protein, 95% CI = -63.3-11.8). This is in line with a positive association between consumption of brassica vegetables and GSTM isoenzyme level [difference between high and low consumption: 67.5%, 95% CI = (6.8-162.7)]. Consumption of allium vegetables was not associated with GST enzyme activity, but negatively with GSTP1-1 levels [difference between high and low consumption: -23.3%, 95% CI = (-35.5; -8.6)]. Associations were similar among those with the GSTT1-plus and GSTT1-null genotype. In conclusion, variations in habitual consumption of fruits, particularly citrus fruits, and of vegetables, in particular brassica vegetables, among those with the GSTM1-plus genotype, may contribute to variations in human rectal GST enzyme activity.
...
PMID:Habitual consumption of fruits and vegetables: associations with human rectal glutathione S-transferase. 1528 78

Hypericin (HYP) is a major constituent of the herbal antidepressant St. John's wort with potential utility as an antitumor photodynamic sensitizer and antiviral agent. Upon irradiation at 540-600 nm, HYP generates reactive oxygen species (ROS) and induces oxidative stress. Here, human glutathione S-transferase (GST) isoforms GSTP1-1 (P1-1) and GSTA1-1 (A1-1) are shown to bind with high affinity to HYP and to differentially quench its photodynamic properties. In steady-state turnover studies, HYP inhibits A1-1 and P1-1 with IC(50) values of 160 and 190 nM, respectively. Fluorescence titration experiments and fitting of the data to the Hill equation yield apparent K(D)s for binding to A1-1 and P1-1 of 0.65 and 0.51 microM, respectively. The recovered Hill coefficients are 1.8 for both GSTA1-1 and GSTP1-1, indicating that multiple HYPs bind to each isoform. This behavior is reminiscent of classic "ligandin" activity of GSTs, wherein nonsubstrate planar aromatic anions are sequestered on, and inhibit, the enzyme. However, HYP complexed with P1-1 is photodynamically attenuated, with minimal protein oxidation. In contrast, light-dependent, oxygen-dependent, oxidation of A1-1 was modest and oxidation of human albumin was extensive in the presence of HYP, as monitored by electrospray mass spectrometry (ESI-MS). A peptide "trap" of diffusive ROS was oxidized extensively upon irradiation of HYP in the presence of albumin but very little in the presence of P1-1 or A1-1. Solute quenching studies were used to probe the accessibility of the bound HYP in each of the protein complexes. The fluorescence of HYP complexed with albumin, A1-1, or P1-1 was quenched by I(-) with quenching rate constants (k(q)) of 1.1 x 10(9), 2.4 x 10(9) and 0.5 x10(9) M(-1) s(-1), respectively, indicating that small molecules such as O(2) have similar diffusional access to the complexed HYP in each of the proteins, eliminating the possibility of differential accessibility of oxygen as the source of a different yield of ROS. This is the first demonstration of a possible antioxidant role for the ligandin activity of GSTs and a striking example of protein-specific effects on hypericin photodynamic activity. Even highly homologous protein isoforms can differentially promote or inhibit photosensitizer activity.
...
PMID:A novel antioxidant role for ligandin behavior of glutathione S-transferases: attenuation of the photodynamic effects of hypericin. 1546 48


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---