Glutathione-S-Transferases: As Signaling Molecules (original) (raw)
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Glutathione S-transferases, structure, regulation, and therapeutic implications
Journal of Biological Chemistry, 1993
The glutathione S-transferases (GSTs)' are a family of enzymes that catalyze the nucleophilic addition of the thiol of reduced glutathione to a variety of electrophiles (1-9). In addition, the GSTs bind with varying affinities a variety of hydrophobic compounds such as heme, bilirubin, polycyclic aromatic hydrocarbons, and dexamethasone (1-9). It is now generally accepted that the GSTs are encoded by at least five different gene families (9-12). Four of the gene families encode the cytosolic GSTs whereas the fifth encodes a microsomal form of the enzyme (13, 14). In this review, we have focused on three GST research areas: 1) structure-function analysis of GSTs; 2) regulation of GST expression; and 3) GSTs as therapeutic targets in disease. Since our review will not be comprehensive, we would like to direct the reader to several excellent recent reviews focusing on various aspects of GSTs (4,8,9).
Antioxidants & Redox Signaling, 2004
A NTIOXIDANTS are important means of negating the deleterious effects of oxidative stress, and are viewed as potential protective agents against age-related degenerative disorders such as atherosclerosis, cataractogenesis, carcinogenesis, Parkinson's disease, and Alzheimer's disease. Unless detoxified, the reactive oxygen species [ROS; e.g., hydrogen peroxide (H 2 O 2 ), superoxide anion (O 2 2 ), hydroxyl (OH )] generated during processes such as mitochondrial electron transport, UV irradiation, inflammation, and metabolism of xenobiotics by the CYP450 system can attack the cellular macromolecules, including DNA, protein, and lipids. The interaction of ROS with lipids is particularly damaging to cells because a single ROS molecule can generate a number of toxicants such as the hydroperoxides, peroxyradicals, alkoxy radicals, and a,b-unsaturated aldehydes due to the autocatalytic propagation of lipid peroxidation reactions. Lipid peroxidation has been implicated in the etiology of age-related degenerative disorders (15, 34, 61,
5 Role of glutathione S-transferase in the cellular antioxidant defence
Glutathione S-transferases (GSTs) are multifunctional and multigene products. GSTs are adaptable enzymes and participate in the nucleophilic attack on the sulphur atom of glutathione on the electrophilic centres of various endogenous and xenobiotic compounds. Through the GSH-dependent peroxidase activity GSTs, have important function in protecting against organic hydroxiperoxides generated during oxidative stress. By quality of their non-enzymically ability to bind hydrophobic compounds,
Glutathione S-transferase Activity in Diagnostic Pathology
Journal of Postgenomics Drug & Biomarker Development, 2015
etc. were used to collate relevant articles. The results were then crossreferenced to generate a total number of 125 references cited in this review. Functions of glutathione S-transferases The functions of GSTs have been classified into two general categories [19,20]. As intracellular binding proteins [2,21,22], GSTs function on a broad scale in solubilizing and transport of substances much as the extracellular functions of albumin described elsewhere [23,24]. The GST from rat liver, designated as transferase B, has been shown to be identical to the bilirubin binding protein or 'ligandins' [25]. Although ligandins have high affinity for endogenous compounds such as bile acids, haemin, bilirubin, fatty acids and steroids [16,18,22], whose conjugates are eventually sequestered [26], the bound GSTs are devoid of catalytic processing and do not form glutathione conjugates with their substrates [18,27]. Another specific protective role of GST as ligandin is the specific binding of intra-erythrocyte GSTP1-1 isoform to Jun-kinase, a pro-apoptotic enzyme that becomes inactive when bound to GST [26,28]. The second major function is the protection of cellular components [29,30] by the preferential reaction of electrophilic agents with GSH through the enzymatic action of GSTs, and thereby prevents the reaction of electrophiles with cellular nucleophiles. The enzyme may also detoxify certain extremely reactive substances by direct covalent binding to electrophilic agents [1,22,31]. For the most part, GSTs catalyze the conjugation of electrophilic groups of hydrophobic drugs and xenobiotics to form glutathione-thioethers [32]. These thioethers are converted to mercapturic acid by the sequential actions of γ-glutamyl transpeptidase, depeptidase and N-acetylase [2,15,33] prior to the eventual elimination of the hydrophilic conjugates. Reactive oxygen and nitrogen species (ROS/RNS) can alter the
GLUTATHIONE S-TRANSFERASES: A BRIEF ON CLASSIFICATION AND GSTM1-T1 ACTIVITY
The glutathione S-transferase (GST) isoenzyme superfamilies detoxify a wide-range of toxic chemicals and environmental substances are extensively expressed in mammalian tissues. Liver and pancreas are the sites where cytosolic Phase I and phase II biotransformation GSTs enzymes have characteristic expression. GSTs play a key role in the deactivation of reactive oxygen species (ROS) and the metabolism of lipids, chemotherapeutic agents. GSTs are mainly involved in conjugation of reduced glutathione (GSH) with diverse substrates specificity and it is possible that genetic variations in these enzymes will influence cellular response to the environmental agents. GSTs are overexpressed in response to a chemical or oxidative stress as an adaptive physiology and upregulated in cancerous state of organ or tissue. GSTs are essentially involved in susceptibility to various forms of cancer as they are vital in detoxification mechanism to metabolize the environmental carcinogens. GSTM1 encodes for a class mu GST isoenzyme involved in polycyclic aromatic hydrocarbons (PAHs) detoxification. The substrates of GSTM1 include benzo(a)pyrene, benzo(c)phenanthrene, benzo(g)chrysene and other carcinogens. They can catalyze in-vitro GSH conjugation with several potent carcinogenic epoxides including aflatoxin B1(AFB1)8,9-epoxide and electrophilic metabolites of PAHs present in tobacco smoke. Ethylene dibromide, p-nitrobenzyl chloride, p-nitrophenetyl bromide, methyl chloride, and methyl iodide, are known substrates for GSTT1 or GST Theta (θ). GST Theta is most primitive among other known GSTs and widely expressed in nature.
Glutathione S-Transferases in Cancer
Antioxidants
In humans, the glutathione S-transferases (GST) protein family is composed of seven members that present remarkable structural similarity and some degree of overlapping functionalities. GST proteins are crucial antioxidant enzymes that regulate stress-induced signaling pathways. Interestingly, overactive GST proteins are a frequent feature of many human cancers. Recent evidence has revealed that the biology of most GST proteins is complex and multifaceted and that these proteins actively participate in tumorigenic processes such as cell survival, cell proliferation, and drug resistance. Structural and pharmacological studies have identified various GST inhibitors, and these molecules have progressed to clinical trials for the treatment of cancer and other diseases. In this review, we discuss recent findings in GST protein biology and their roles in cancer development, their contribution in chemoresistance, and the development of GST inhibitors for cancer treatment.
2018
The present study was aimed to analyse the effect of acrylamide and Hybanthus enneaspermus leaf extract active principles on mice testis glutathione-s-transferases (GST; EC 2.5.1.18). These enzymes play a role in biotransformation of electrophilic compounds that cause damage to cells by conjugating with the substrate glutathione. Hybanthus enneaspermus, a spade flower, is an erect shrub of violaceae family, having free radical scavenging activity. Acrylamide is a known neurotoxicant that cause damage to almost all cells including liver, testis, brain and kidney. The GSTs purified from mice testis using glutathionyl linked agarose affinity chromatography were analyzed by using SDS-PAGE and were resolved into four sub units i.e. Yc, Yb, Yβ &Yδ. Also these subunits expression were confirmed by western blot analysis. During experimentation to analyze the effect of Hybanthus enneaspermus active principle (HE) mice were subjected to both acrylamide (AC) and also mixture of HE and AC. This exposure significantly altered the specific activity of mice GSTs in testis. Polyclonal antibodies produced against purified GSTs of mice testis on immunoblot analysis showed significant increase of µclass GSTs (Yb & Yβ) based on dose and time dependent manner. Therefore the present research of Hybanthus enneaspermus treatment on mice testis showed that, regulation of synthesis of µ-GSTs was depending on the dose of acrylamide concentration and also the active principles of HE. Hence it is proposed that µ-GSTs may be used as tumour markers for testis carcinoma, since their production is variable due to the increased dose concentration of synthetic chemical acrylamide and its regulation by plant product, HE.
Archives of Biochemistry and Biophysics, 1999
In order to elucidate the protective role of glutathione S-transferases (GSTs) against oxidative stress, we have investigated the kinetic properties of the human ␣-class GSTs, hGSTA1-1 and hGSTA2-2, toward physiologically relevant hydroperoxides and have studied the role of these enzymes in glutathione (GSH)-dependent reduction of these hydroperoxides in human liver. We have cloned hGSTA1-1 and hGSTA2-2 from a human lung cDNA library and expressed both in Escherichia coli. Both isozymes had remarkably high peroxidase activity toward fatty acid hydroperoxides, phospholipid hydroperoxides, and cumene hydroperoxide. In general, the activity of hGSTA2-2 was higher than that of hGSTA1-1 toward these substrates. For example, the catalytic efficiency (k cat /K m) of hGSTA1-1 for phosphatidylcholine (PC) hydroperoxide and phosphatidylethanolamine (PE) hydroperoxide was found to be 181.3 and 199.6 s ؊1 mM ؊1 , respectively, while the catalytic efficiency of hGSTA2-2 for PC-hydroperoxide and PE-hydroperoxide was 317.5 and 353 s ؊1 mM ؊1 , respectively. Immunotitration studies with human liver extracts showed that the antibodies against human ␣-class GSTs immunoprecipitated about 55 and 75% of glutathione peroxidase (GPx) activity of human liver toward PC-hydroperoxide and cumene hydroperoxide, respectively. GPx activity was not immunoprecipitated by the same antibodies from human erythrocyte hemolysates. These results show that the ␣-class GSTs contribute a major portion of GPx activity toward lipid hydroperoxides in human liver. Our results also suggest that GSTs may be involved in the reduction of 5-hydroperoxyeicosatetrae-noic acid, an important intermediate in the 5-lipoxygenase pathway.
FEBS Journal, 2011
Glutathione (GSH) conjugating enzymes, glutathione S-transferases (GSTs) are present in different subcellular compartments including cytosol, mitochondria, endoplasmic reticulum, nucleus and plasma membrane. The regulation and function of GSTs have implications in cell growth, oxidative stress, as well as in disease progression and prevention. Of the several mitochondria localized forms, GSTK (GST kappa) is mitochondria-specific since it contains Nterminal canonical and cleavable mitochondria targeting signal. Other forms, like GST alpha, mu and pi purified from mitochondria are similar to the cytosolic molecular forms or "echoproteins". Altered GST expression has been implicated in hepatic, cardiac and neurological diseases. Mitochondria-specific GSTK has also been implicated in obesity, diabetes and related metabolic disorders. Studies have shown that silencing the GSTA4 (GST alpha) gene resulted in mitochondrial dysfunction, as was also seen in GSTA4 null mice which could contribute to insulin resistance in type 2 diabetes. This review highlights the significance of mitochondrial GST pool, particularly the mechanism and significance of dual targeting of GSTA4-4 under in vitro and in vivo conditions. GSTA4-4 is targeted in the mitochondria by activation of the internal cryptic signal present at the C-terminus of the protein by protein kinase-dependent phosphorylation and cytosolic heat shock protein (Hsp70) chaperon. Mitochondrial GSTpi, on the other hand, has been shown to have two uncleaved cryptic signals rich in positively charged amino acids at the Nterminal region. Both physiological and pathophysiological implications of GST translocation to mitochondria have been discussed in this review.