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)

Binding and catalytic properties of glutathione S-transferase from Plasmodium falciparum (PfGST) have been studied by means of fluorescence, steady state and pre-steady state kinetic experiments, and docking simulations. This enzyme displays a peculiar reversible low-high affinity transition, never observed in other GSTs, which involves the G-site and shifts the apparent K(D) for glutathione (GSH) from 200 to 0.18 mM. The transition toward the high affinity conformation is triggered by the simultaneous binding of two GSH molecules to the dimeric enzyme, and it is manifested as an uncorrected homotropic behavior, termed "pseudo-cooperativity." The high affinity enzyme is able to activate GSH, lowering its pK(a) value from 9.0 to 7.0, a behavior similar to that found in all known GSTs. Using 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, this enzyme reveals a potential optimized mechanism for the GSH conjugation but a low catalytic efficiency mainly due to a very low affinity for this co-substrate. Conversely, PfGST efficiently binds one molecule of hemin/monomer. The binding is highly cooperative (n(H) = 1.8) and occurs only when GSH is bound to the enzyme. The thiolate of GSH plays a crucial role in the intersubunit communication because no cooperativity is observed when S-methylglutathione replaces GSH. Docking simulations suggest that hemin binds to a pocket leaning into both the G-site and the H-site. The iron is coordinated by the amidic nitrogen of Asn-115, and the two carboxylate groups are in electrostatic interaction with the epsilon-amino group of Lys-15. Kinetic and structural data suggest that PfGST evolved by optimizing its binding property with the parasitotoxic hemin rather than its catalytic efficiency toward toxic electrophilic compounds.
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PMID:Cooperativity and pseudo-cooperativity in the glutathione S-transferase from Plasmodium falciparum. 1588 43

The control of size and size distribution of microspheres is necessary for obtaining repeatable controlled release behavior. The chitosan microspheres were prepared by a membrane emulsification technique in this study. Chitosan was dissolved in 1 wt.% aqueous acetic acid containing 0.9 wt.% sodium chloride, which was used as a water phase. A mixture of liquid paraffin and petroleum ether 7:5 (v/v) containing PO-500 emulsifier was used as an oil phase. The water phase was permeated through the uniform pores of a porous glass membrane into the oil phase by the pressure of nitrogen gas to form W/O emulsion. Then GST (Glutaraldehyde Saturated Toluene) as crosslinking agent was slowly dropped into the W/O emulsion to solidify the chitosan droplets. The preparation condition for obtaining uniform-sized microspheres was optimized. The microspheres with different size were prepared by using the membranes with different pore size, and there was a linear relationship between the diameter of microspheres and pore size of the membranes when the microspheres were in the range of micron size. The smallest chitosan microspheres obtained was 0.4 mum in diameter. This is the first report for preparing the uniform-sized chitosan microspheres by membrane emulsification technique. Uniform chitosan microspheres were further used as a carrier of protein drug. Bovine serum albumin (BSA) as a model drug was loaded in the microspheres and released in vitro. The effects of pH value, diameter and crosslinking degree of microspheres, and BSA concentration on loading efficiency and release behavior were discussed.
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PMID:Preparation of uniform sized chitosan microspheres by membrane emulsification technique and application as a carrier of protein drug. 1592 72

7,12-Dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon (PAH), has been used extensively as a tool to initiate mammary carcinogenesis and subsequent chemoprevention. On the other hand, selenium (Se) is potentially useful in oncology because this element possesses anticarcinogenic and chemopreventive properties. Se-containing enzymes such as glutathione peroxidase (GPx) play an important role in PAH metabolism and detoxification. In this study, rats were administered a single, oral dose of DMBA (12 mg). In the Se group, rats received 20 microg Se daily via gavage, starting 2 wk before the DMBA administration and continued for 1 wk. One hundred twenty days after DMBA administration the rats were sacrificed and toxicity was evaluated using histopathological and biochemical criteria. Five rats (30%) died in the DMBA group within the study period, whereas no death occurred in the DMBA-Se-treated group. Malignant tumor frequency was 33% in the DMBA group, while no malignant tumors occurred in the DMBA-Se-treated group. Some inflammatory changes rather than epithelial changes were found upon histopathological examination. GPx activity and blood urea nitrogen levels were higher and kidney GST activity was lower in the DMBA-Se-treated group compared to DMBA alone. In conclusion, Se appears to be effective in preventing some of the adverse effects associated with DMBA.
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PMID:Toxicity induced by the chemical carcinogen 7,12-dimethylbenz[a]anthracene and the protective effects of selenium in Wistar rats. 1602 Jan 97

The lungs of asthmatic patients are exposed to oxidative stress due to the generation of reactive oxygen and nitrogen species as a consequence of chronic airway inflammation. Increased concentrations of NO*, H2O2 and 8-isoprostane have been measured in exhaled breath and induced sputum of asthmatic patients. O2*-, NO*, and halides interact to form highly reactive species such as peroxynitrite and HOBr, which in turn cause nitration and bromination of protein tyrosine residues. Oxidative stress may also reduce glutathione levels and cause inactivation of antioxidant enzymes such as superoxide dismutase, with a consequent increase in apoptosis, shedding of airway epithelial cells and airway remodelling. The oxidant/antioxidant equilibrium in asthmatic patients may be further perturbed by low dietary intakes of the antioxidant vitamins C and E, selenium and flavonoids, with a consequent lowering of the concentrations of these and other non-dietary antioxidants such as bilirubin and albumin in plasma and airway epithelial lining fluid. Although supplementation with vitamins C and E appears to offer protection against the adverse effects of ozone, recent randomised, placebo-controlled trials of vitamin C or E supplements for patients with mild asthma have not shown significant benefits over standard therapy. However, genetic variation in glutathione S-transferase may influence the susceptibility of asthmatic individuals to oxidative stress and the extent to which they are likely to benefit from antioxidant supplementation. Long-term prospective trials are required to determine whether modification of dietary intake will benefit asthma patients and reduce the socio-economic burden of asthma in the community.
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PMID:Oxidative stress and antioxidant deficiencies in asthma: potential modification by diet. 1635 13

The importance of nitric oxide (NO) in regulating plant cell responses to environmental stresses is becoming evident. Here the possible role of NO in suspension cultures of Taxus cuspidata under shear stress was investigated in a Couette-type shear reactor. It was found that shear stress with 190 s(-1) caused NO generation in 8 h. NO formation can be inhibited by N-nitro-L-arginine, a nitric oxide synthase inhibitor. Moreover, the activity of glutathione S-transferase (GST), a principal enzyme responsible for detoxification, decreased during shear stress. This inactivation partially recovered when NOS inhibitor or NO scavenger was added into cell cultures during shear stress. Treatment with reactive nitrogen species (RNS) also caused inactivation of GST in cells. The results indicate that NO plays a crucial role in GST inactivation in Taxus cuspidata cells under shear stress.
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PMID:Nitric oxide mediates inactivation of glutathione S-transferase in suspension culture of Taxus cuspidata during shear stress. 1635 47

The activities of antioxidant enzymes viz. glutathione reductase, GR; superoxide dismutase, SOD; peroxidase, POD; catalase, CAT and glutathione-S-transferase, GST and alkaloid accumulation were investigated in leaf pairs (apical, middle, basal) and in roots of Catharanthus roseus seedlings under the conditions of different nitrogen sources (20 mM KNO(3) and 2 mM NH(4)Cl) and salinity, in the absence (non-saline control) and in the presence of 100 mM NaCl in the nutrient solution. Salinity caused a reduction in plant biomass. The biomass production of ammonium-fed plants was lower than that of nitrate-fed plants. The antioxidant enzymes exhibited higher activity in saline-treated plants. Changes in antioxidant enzyme activity caused by different nitrogen sources differed in all leaf pairs, as well as in roots of C. roseus. Ammonium-fed plants showed higher CAT, GR and GST activity in leaf pairs as well as in roots, while POD and SOD activity were higher in nitrate-fed plants. Higher peroxidase activity concomitant with the increased accumulation of alkaloid was found in all leaf pairs, as well as in roots of C. roseus of NO(3)(-) fed plants as compared to NH(4)(+) fed plants.
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PMID:Effect of salinity and different nitrogen sources on the activity of antioxidant enzymes and indole alkaloid content in Catharanthus roseus seedlings. 1636 Jul 99

The effect of reactive nitrogen species on rat liver microsomal glutathione S-transferase (MGST1) was investigated using microsomes and purified MGST1. When microsomes or the purified enzyme were incubated with peroxynitrite (ONOO(-)), the GST activity was increased to 2.5-6.5 fold in concentration-dependent manner and a small amount of the MGST1 dimer was detected. MGST1 activity was increased by ONOO(-) in the presence of high amounts of reducing agents including glutathione (GSH) and the activities increased by ONOO(-) or ONOO(-) plus GSH treatment were decreased by 30-40% by further incubation with dithiothreitol (DTT, reducing disulfide) or by sodium arsenite (reducing sulfenic acid). Furthermore, GSH was detected by HPLC from the MGST1 which was incubated with ONOO(-) plus GSH or S-nitrosoglutathione followed by DTT treatment. In addition, the MGST1 activity increased by nitric oxide (NO) donors such as S-nitrosoglutathione, S-nitrosocysteine or the non-thiol NO donor 1-hydroxy-2-oxo-3 (3-aminopropyl)-3-isopropyl was restored by the DTT treatment. Since DTT can reduce S-nitrosothiol and disulfide bond to thiol, S-nitrosylation and a mixed disulfide bond formation of MGST1 were suggested. Thus, it was demonstrated that MGST1 is activated by reactive nitrogen species through a forming dimeric protein, mixed disulfide bond, nitrosylation and sulfenic acid.
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PMID:Reactive nitrogen species derived activation of rat liver microsomal glutathione S-transferase. 1638 61

We investigated the in vitro metabolism of two (nitrooxy)butyl ester nitric oxide (NO) donor derivatives of flurbiprofen and ferulic acid, [1,1'-biphenyl]-4-acetic acid-2-fluoro-alpha-methyl-4-(nitrooxy)butyl ester (HCT 1026) and 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-(nitrooxy)butyl ester (NCX 2057), respectively, in rat blood plasma and liver subcellular fractions compared with (nitrooxy)butyl alcohol (NOBA) and glyceryl trinitrate (GTN). HCT 1026 and NCX 2057 undergo rapid ubiquitous carboxyl ester hydrolysis to their respective parent compounds and NOBA. The nitrate moiety of this latter is subsequently metabolized to inorganic nitrogen oxides (NOx), predominantly in liver cytosol by glutathione S-transferase (GST) and to a lesser extent in liver mitochondria. If, however, in liver cytosol, the carboxyl ester hydrolysis is prevented by an esterase inhibitor, the metabolism at the nitrate moiety level does not occur. In blood plasma, HCT 1026 and NCX 2057 are not metabolized to NOx, whereas a slow but sustained NO generation in deoxygenated whole blood as detected by electron paramagnetic resonance indicates the involvement of erythrocytes in the bioactivation of these compounds. Differently from NOBA, GTN is also metabolized in blood plasma and more quickly metabolized by different GST isoforms in liver cytosol. The cytosolic GST-mediated denitration of these organic nitrates in liver limits their interaction with other intracellular compartments to possible generation of NO and/or their subsequent availability and bioactivation in the systemic circulation and extrahepatic tissues. We show the possibility of modulating the activity of hepatic cytosolic enzymes involved in the metabolism of (nitrooxy)butyl ester compounds, thus increasing the therapeutic potential of this class of compounds.
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PMID:In vitro metabolism of (nitrooxy)butyl ester nitric oxide-releasing compounds: comparison with glyceryl trinitrate. 1642 50

Aging is accompanied by changes in the morphology and physiology of organs and tissues, such as the liver. This process might be due to the accumulation of oxidative damage induced by reactive oxygen (ROS) and reactive nitrogen species (RNS). Hepatocytes are very rich in mitochondria and have a high respiratory rate, so they are exposed to large amounts of ROS and permanent oxidative stress. Twenty-four male Wistar rats of 22 months of age were divided into three groups. One group remained untreated and acted as the control group. The second was treated with growth hormone (GH) (2 mg/kg/d sc) and the third was submitted to treatment wit 1 mg/kg/d of melatonin in the drinking water. A group of 2-months-old male rats was used as young controls. After 10 wk of treatment the rats were killed by decapitation, and the liver was dissected and homogenized. Mitochondrial, cytosolic and microsomal fractions were obtained and cytochrome C, glutathione peroxidase, s-transferase and nitric oxide (NO) were measured. Aging induced a significant increase in mitochondrial nitric oxide. An increase in cytochrome C in the cytosolic fraction and a reduction in the mitochondrial fraction with age was also observed. Both GH and melatonin treatments significantly reduced the enhanced measures and increased the reduced values. A reduction in glutathione peroxidase and glutathione S-transferase was found in old control rats when compared with the group of young animals. Treatment for 2.5 months of old rats with GH and melatonin were able to increase the enzymes reaching values similar to those found in young animals. In conclusion, GH and melatonin treatment seems to have beneficial effects against age-induced damage in the liver.
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PMID:Effect of exogenous administration of melatonin and growth hormone on pro-antioxidant functions of the liver in aging male rats. 1719 40

Substantial evidence suggests a crucial role for glutathione (GSH) and GSH-linked enzymes in protecting against oxidative vascular disorders. However, studies on the chemical inducibility of these antioxidant defenses and their protective effects on oxidant injury in normal human vascular cells are currently lacking. Accordingly, this study was undertaken to investigate the inducibility of GSH, glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione S-transferase (GST) by the chemoprotective agent, 3H-1,2-dithiole-3-thione (D3T) in cultured normal human aortic smooth muscle cells (HASMCs). HASMCs expressed measurable levels/activities of GSH, GR, GPx, and GST. Incubation of HASMCs with low micromolar concentrations of D3T resulted in a marked elevation in total cellular GSH content and GR activity. The protein and mRNA expression of gamma-glutamylcysteine ligase (GCL) and GR were also upregulated by D3T. In addition, D3T caused significant increases in mitochondrial GSH content and GR activity. In contrast, neither cellular GPx nor GST activity was altered after D3T treatment. Pretreatment of HASMCs with D3T afforded remarkable protection against reactive oxygen and nitrogen species (ROS/RNS)-mediated cell injury. Depletion of cellular GSH by pretreatment with buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis led to marked potentiation of the ROS/RNS-induced cell injury. Moreover, co-treatment of HASMCs with BSO was found to completely abolish the D3T-mediated GSH elevation, and remarkably reverse D3T cytoprotection against the ROS/RNS-elicited injury. Taken together, this study demonstrates that both GSH/GCL and GR in normal HASMCs are inducible by D3T, and that upregulation of GSH biosynthesis appears to be the predominant mechanism underlying D3T-mediated cytoprotection against ROS/RNS-elicited injury to human vascular smooth muscle cells.
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PMID:Glutathione and glutathione-linked enzymes in normal human aortic smooth muscle cells: chemical inducibility and protection against reactive oxygen and nitrogen species-induced injury. 1720 82


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