Versatility of Glutathione Transferase Proteins

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 23653

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Department of Biochemistry and Biophysics, Stockholm University, Arrhenius Laboratories, SE-10691 Stockholm, Sweden
Interests: enzymology; glutathione transferase; cellular signaling

Special Issue Information

Dear Colleagues,

Glutathione is an abundant tripeptide in essentially all aerobic organisms and a pivotal component in cellular protection against oxidative stress, electrophilic mutagens, and carcinogens. Glutathione transferases (GSTs) are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of the toxic compounds followed by subsequent excretion of the detoxified products. GSTs occur abundantly in multiple forms, and the “GSTome” encompasses both soluble and membrane-bound proteins. Discovered as enzymes detoxifying xenobiotics, including pesticides and herbicides, it was later found that natural substrates include products of lipid peroxidation and other toxic compounds derived from endogenous cellular components. GSTs can be secreted from cells in culture and taken up in catalytically functional form by other cells, suggesting intracellular trafficking in tissues. GST functions include metabolic reactions such as steroid double-bond isomerization in sex hormone production as well as intracellular transport of ligands. Another aspect of GST functionality involves the regulation of cellular signaling via binding to protein kinases such as AKT and JNK. This aspect is consequential to the proliferation and suppression of cancer cells, and genetic polymorphisms in the GSTome influence susceptibility to disease. Prodrugs have been designed to be activated in tumors by their intrinsic GSTs. Engineering of GSTs for biotechnical applications is in progress.

Over many decades, GSTs have attracted increased attention, but the research field of the GSTome has not yet matured. New aspects continue to emerge, and a full understanding of the scope of the GST proteins is not yet in sight.

Prof. Dr. Bengt Mannervik
Guest Editor

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Keywords

  • glutathione
  • glutathione transferase
  • GST
  • detoxication
  • cellular signaling
  • enzyme evolution

Published Papers (11 papers)

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Editorial

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4 pages, 216 KiB  
Editorial
Versatility of Glutathione Transferase Proteins
by Bengt Mannervik
Biomolecules 2023, 13(12), 1749; https://doi.org/10.3390/biom13121749 - 06 Dec 2023
Viewed by 776
Abstract
For more than 60 years, glutathione transferases (GSTs) have attracted attention, but the research field of the GSTome [...] Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)

Research

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15 pages, 2277 KiB  
Article
Conservation of Glutathione Transferase mRNA and Protein Sequences Similar to Human and Horse Alpha Class GST A3-3 across Dog, Goat, and Opossum Species
by Shawna M. Hubert, Paul B. Samollow, Helena Lindström, Bengt Mannervik and Nancy H. Ing
Biomolecules 2023, 13(9), 1420; https://doi.org/10.3390/biom13091420 - 20 Sep 2023
Cited by 2 | Viewed by 999
Abstract
The glutathione transferase A3-3 (GST A3-3) homodimeric enzyme is the most efficient enzyme that catalyzes isomerization of the precursors of testosterone, estradiol, and progesterone in the gonads of humans and horses. However, the presence of GST A3-3 orthologs with equally high ketosteroid isomerase [...] Read more.
The glutathione transferase A3-3 (GST A3-3) homodimeric enzyme is the most efficient enzyme that catalyzes isomerization of the precursors of testosterone, estradiol, and progesterone in the gonads of humans and horses. However, the presence of GST A3-3 orthologs with equally high ketosteroid isomerase activity has not been verified in other mammalian species, even though pig and cattle homologs have been cloned and studied. Identifying GSTA3 genes is a challenge because of multiple GSTA gene duplications (e.g., 12 in the human genome); consequently, the GSTA3 gene is not annotated in most genomes. To improve our understanding of GSTA3 gene products and their functions across diverse mammalian species, we cloned homologs of the horse and human GSTA3 mRNAs from the testes of a dog, goat, and gray short-tailed opossum, the genomes of which all currently lack GSTA3 gene annotations. The resultant novel GSTA3 mRNA and inferred protein sequences had a high level of conservation with human GSTA3 mRNA and protein sequences (≥70% and ≥64% identities, respectively). Sequence conservation was also apparent for the 12 residues of the “H-site” in the 222 amino acid GSTA3 protein that is known to interact with the steroid substrates. Modeling predicted that the dog GSTA3-3 may be a more active ketosteroid isomerase than the corresponding goat or opossum enzymes. However, expression of the GSTA3 gene was higher in liver than in other dog tissue. Our results improve understanding of the active sites of mammalian GST A3-3 enzymes, inhibitors of which might be useful for reducing steroidogenesis for medical purposes, such as fertility control or treatment of steroid-dependent diseases. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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19 pages, 6804 KiB  
Article
Hidden Glutathione Transferases in the Human Genome
by Aaron J. Oakley
Biomolecules 2023, 13(8), 1240; https://doi.org/10.3390/biom13081240 - 12 Aug 2023
Cited by 1 | Viewed by 1101
Abstract
With the development of accurate protein structure prediction algorithms, artificial intelligence (AI) has emerged as a powerful tool in the field of structural biology. AI-based algorithms have been used to analyze large amounts of protein sequence data including the human proteome, complementing experimental [...] Read more.
With the development of accurate protein structure prediction algorithms, artificial intelligence (AI) has emerged as a powerful tool in the field of structural biology. AI-based algorithms have been used to analyze large amounts of protein sequence data including the human proteome, complementing experimental structure data found in resources such as the Protein Data Bank. The EBI AlphaFold Protein Structure Database (for example) contains over 230 million structures. In this study, these data have been analyzed to find all human proteins containing (or predicted to contain) the cytosolic glutathione transferase (cGST) fold. A total of 39 proteins were found, including the alpha-, mu-, pi-, sigma-, zeta- and omega-class GSTs, intracellular chloride channels, metaxins, multisynthetase complex components, elongation factor 1 complex components and others. Three broad themes emerge: cGST domains as enzymes, as chloride ion channels and as protein–protein interaction mediators. As the majority of cGSTs are dimers, the AI-based structure prediction algorithm AlphaFold-multimer was used to predict structures of all pairwise combinations of these cGST domains. Potential homo- and heterodimers are described. Experimental biochemical and structure data is used to highlight the strengths and limitations of AI-predicted structures. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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10 pages, 1737 KiB  
Article
Potent GST Ketosteroid Isomerase Activity Relevant to Ecdysteroidogenesis in the Malaria Vector Anopheles gambiae
by Yaman Musdal, Aram Ismail, Birgitta Sjödin and Bengt Mannervik
Biomolecules 2023, 13(6), 976; https://doi.org/10.3390/biom13060976 - 11 Jun 2023
Cited by 2 | Viewed by 1339
Abstract
Nobo is a glutathione transferase (GST) crucially contributing to ecdysteroid biosynthesis in insects of the orders Diptera and Lepidoptera. Ecdysone is a vital steroid hormone in insects, which governs larval molting and metamorphosis, and the suppression of its synthesis has potential as [...] Read more.
Nobo is a glutathione transferase (GST) crucially contributing to ecdysteroid biosynthesis in insects of the orders Diptera and Lepidoptera. Ecdysone is a vital steroid hormone in insects, which governs larval molting and metamorphosis, and the suppression of its synthesis has potential as a novel approach to insect growth regulation and combatting vectors of disease. In general, GSTs catalyze detoxication, whereas the specific function of Nobo in ecdysteroidogenesis is unknown. We report that Nobo from the malaria-spreading mosquito Anopheles gambiae is a highly efficient ketosteroid isomerase catalyzing double-bond isomerization in the steroids 5-androsten-3,17-dione and 5-pregnen-3,20-dione. These mammalian ketosteroids are unknown in mosquitoes, but the discovered prominent catalytic activity of these compounds suggests that the unknown Nobo substrate in insects has a ketosteroid functionality. Aminoacid residue Asp111 in Nobo is essential for activity with the steroids, but not for conventional GST substrates. Further characterization of Nobo may guide the development of new insecticides to prevent malaria. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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15 pages, 3099 KiB  
Article
Inhibition Analysis and High-Resolution Crystal Structure of Mus musculus Glutathione Transferase P1-1
by Oleksii Kupreienko, Fotini Pouliou, Konstantinos Konstandinidis, Irene Axarli, Eleni Douni, Anastassios C. Papageorgiou and Nikolaos E. Labrou
Biomolecules 2023, 13(4), 613; https://doi.org/10.3390/biom13040613 - 29 Mar 2023
Cited by 2 | Viewed by 1934
Abstract
Multidrug resistance is a significant barrier that makes anticancer therapies less effective. Glutathione transferases (GSTs) are involved in multidrug resistance mechanisms and play a significant part in the metabolism of alkylating anticancer drugs. The purpose of this study was to screen and select [...] Read more.
Multidrug resistance is a significant barrier that makes anticancer therapies less effective. Glutathione transferases (GSTs) are involved in multidrug resistance mechanisms and play a significant part in the metabolism of alkylating anticancer drugs. The purpose of this study was to screen and select a lead compound with high inhibitory potency against the isoenzyme GSTP1-1 from Mus musculus (MmGSTP1-1). The lead compound was selected following the screening of a library of currently approved and registered pesticides that belong to different chemical classes. The results showed that the fungicide iprodione [3-(3,5-dichlorophenyl)-2,4-dioxo-N-propan-2-ylimidazolidine-1-carboxamide] exhibited the highest inhibition potency (ΙC50 = 11.3 ± 0.5 μΜ) towards MmGSTP1-1. Kinetics analysis revealed that iprodione functions as a mixed-type inhibitor towards glutathione (GSH) and non-competitive inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). X-ray crystallography was used to determine the crystal structure of MmGSTP1-1 at 1.28 Å resolution as a complex with S-(p-nitrobenzyl)glutathione (Nb-GSH). The crystal structure was used to map the ligand-binding site of MmGSTP1-1 and to provide structural data of the interaction of the enzyme with iprodione using molecular docking. The results of this study shed light on the inhibition mechanism of MmGSTP1-1 and provide a new compound as a potential lead structure for future drug/inhibitor development. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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15 pages, 1448 KiB  
Article
Reversibility and Low Commitment to Forward Catalysis in the Conjugation of Lipid Alkenals by Glutathione Transferase A4-4
by Michele Scian, Lorela Paço, Taylor A. Murphree, Laura M. Shireman and William M. Atkins
Biomolecules 2023, 13(2), 329; https://doi.org/10.3390/biom13020329 - 09 Feb 2023
Cited by 2 | Viewed by 1368
Abstract
High concentrations of electrophilic lipid alkenals formed during oxidative stress are implicated in cytotoxicity and disease. However, low concentrations of alkenals are required to induce antioxidative stress responses. An established clearance pathway for lipid alkenals includes conjugation to glutathione (GSH) via Michael addition, [...] Read more.
High concentrations of electrophilic lipid alkenals formed during oxidative stress are implicated in cytotoxicity and disease. However, low concentrations of alkenals are required to induce antioxidative stress responses. An established clearance pathway for lipid alkenals includes conjugation to glutathione (GSH) via Michael addition, which is catalyzed mainly by glutathione transferase isoform A4 (GSTA4-4). Based on the ability of GSTs to catalyze hydrolysis or retro-Michael addition of GSH conjugates, and the antioxidant function of low concentrations of lipid alkenals, we hypothesize that GSTA4-4 contributes a homeostatic role in lipid metabolism. Enzymatic kinetic parameters for retro-Michael addition with trans-2-Nonenal (NE) reveal the chemical competence of GSTA4-4 in this putative role. The forward GSTA4-4-catalyzed Michael addition occurs with the rapid exchange of the C2 proton of NE in D2O as observed by NMR. The isotope exchange was completely dependent on the presence of GSH. The overall commitment to catalysis, or the ratio of first order kcat,f for ‘forward’ Michael addition to the first order kcat,ex for H/D exchange is remarkably low, approximately 3:1. This behavior is consistent with the possibility that GSTA4-4 is a regulatory enzyme that contributes to steady-state levels of lipid alkenals, rather than a strict ‘one way’ detoxication enzyme. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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19 pages, 7297 KiB  
Article
Biochemical and Structural Characterization of Chi-Class Glutathione Transferases: A Snapshot on the Glutathione Transferase Encoded by sll0067 Gene in the Cyanobacterium Synechocystis sp. Strain PCC 6803
by Eva Mocchetti, Laura Morette, Guillermo Mulliert, Sandrine Mathiot, Benoît Guillot, François Dehez, Franck Chauvat, Corinne Cassier-Chauvat, Céline Brochier-Armanet, Claude Didierjean and Arnaud Hecker
Biomolecules 2022, 12(10), 1466; https://doi.org/10.3390/biom12101466 - 13 Oct 2022
Cited by 2 | Viewed by 1774
Abstract
Glutathione transferases (GSTs) constitute a widespread superfamily of enzymes notably involved in detoxification processes and/or in specialized metabolism. In the cyanobacterium Synechocsytis sp. PCC 6803, SynGSTC1, a chi-class GST (GSTC), is thought to participate in the detoxification process of methylglyoxal, a toxic by-product [...] Read more.
Glutathione transferases (GSTs) constitute a widespread superfamily of enzymes notably involved in detoxification processes and/or in specialized metabolism. In the cyanobacterium Synechocsytis sp. PCC 6803, SynGSTC1, a chi-class GST (GSTC), is thought to participate in the detoxification process of methylglyoxal, a toxic by-product of cellular metabolism. A comparative genomic analysis showed that GSTCs were present in all orders of cyanobacteria with the exception of the basal order Gloeobacterales. These enzymes were also detected in some marine and freshwater noncyanobacterial bacteria, probably as a result of horizontal gene transfer events. GSTCs were shorter of about 30 residues compared to most cytosolic GSTs and had a well-conserved SRAS motif in the active site (10SRAS13 in SynGSTC1). The crystal structure of SynGSTC1 in complex with glutathione adopted the canonical GST fold with a very open active site because the α4 and α5 helices were exceptionally short. A transferred multipolar electron-density analysis allowed a fine description of the solved structure. Unexpectedly, Ser10 did not have an electrostatic influence on glutathione as usually observed in serinyl-GSTs. The S10A variant was only slightly less efficient than the wild-type and molecular dynamics simulations suggested that S10 was a stabilizer of the protein backbone rather than an anchor site for glutathione. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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Review

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17 pages, 1129 KiB  
Review
The Multifaceted Role of Glutathione S-Transferases in Health and Disease
by Aslam M. A. Mazari, Leilei Zhang, Zhi-Wei Ye, Jie Zhang, Kenneth D. Tew and Danyelle M. Townsend
Biomolecules 2023, 13(4), 688; https://doi.org/10.3390/biom13040688 - 18 Apr 2023
Cited by 23 | Viewed by 5007
Abstract
In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by [...] Read more.
In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by protecting living cells against a wide variety of toxic molecules by conjugating them with the tripeptide glutathione. This conjugation reaction is extended to forming redox sensitive post-translational modifications on proteins: S-glutathionylation. Apart from these catalytic functions, specific GSTs are involved in the regulation of stress-induced signaling pathways that govern cell proliferation and apoptosis. Recently, studies on the effects of GST genetic polymorphisms on COVID-19 disease development revealed that the individuals with higher numbers of risk-associated genotypes showed higher risk of COVID-19 prevalence and severity. Furthermore, overexpression of GSTs in many tumors is frequently associated with drug resistance phenotypes. These functional properties make these proteins promising targets for therapeutics, and a number of GST inhibitors have progressed in clinical trials for the treatment of cancer and other diseases. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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12 pages, 902 KiB  
Review
Compounds Inhibiting Noppera-bo, a Glutathione S-transferase Involved in Insect Ecdysteroid Biosynthesis: Novel Insect Growth Regulators
by Kana Ebihara and Ryusuke Niwa
Biomolecules 2023, 13(3), 461; https://doi.org/10.3390/biom13030461 - 02 Mar 2023
Cited by 4 | Viewed by 2747
Abstract
Glutathione S-transferases (GSTs) are conserved in a wide range of organisms, including insects. In 2014, an epsilon GST, known as Noppera-bo (Nobo), was shown to regulate the biosynthesis of ecdysteroid, the principal steroid hormone in insects. Studies on fruit flies, Drosophila melanogaster [...] Read more.
Glutathione S-transferases (GSTs) are conserved in a wide range of organisms, including insects. In 2014, an epsilon GST, known as Noppera-bo (Nobo), was shown to regulate the biosynthesis of ecdysteroid, the principal steroid hormone in insects. Studies on fruit flies, Drosophila melanogaster, and silkworms, Bombyx mori, demonstrated that loss-of-function mutants of nobo fail to synthesize ecdysteroid and die during development, consistent with the essential function of ecdysteroids in insect molting and metamorphosis. This genetic evidence suggests that chemical compounds that inhibit activity of Nobo could be insect growth regulators (IGRs) that kill insects by disrupting their molting and metamorphosis. In addition, because nobo is conserved only in Diptera and Lepidoptera, a Nobo inhibitor could be used to target IGRs in a narrow spectrum of insect taxa. Dipterans include mosquitoes, some of which are vectors of diseases such as malaria and dengue fever. Given that mosquito control is essential to reduce mosquito-borne diseases, new IGRs that specifically kill mosquito vectors are always in demand. We have addressed this issue by identifying and characterizing several chemical compounds that inhibit Nobo protein in both D. melanogaster and the yellow fever mosquito, Aedes aegypti. In this review, we summarize our findings from the search for Nobo inhibitors. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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18 pages, 661 KiB  
Review
Role of Insect and Mammal Glutathione Transferases in Chemoperception
by Mathieu Schwartz, Valentin Boichot, Stéphane Fraichard, Mariam Muradova, Patrick Senet, Adrien Nicolai, Frederic Lirussi, Mathilde Bas, Francis Canon, Jean-Marie Heydel and Fabrice Neiers
Biomolecules 2023, 13(2), 322; https://doi.org/10.3390/biom13020322 - 08 Feb 2023
Cited by 5 | Viewed by 2351
Abstract
Glutathione transferases (GSTs) are ubiquitous key enzymes with different activities as transferases or isomerases. As key detoxifying enzymes, GSTs are expressed in the chemosensory organs. They fulfill an essential protective role because the chemosensory organs are located in the main entry paths of [...] Read more.
Glutathione transferases (GSTs) are ubiquitous key enzymes with different activities as transferases or isomerases. As key detoxifying enzymes, GSTs are expressed in the chemosensory organs. They fulfill an essential protective role because the chemosensory organs are located in the main entry paths of exogenous compounds within the body. In addition to this protective function, they modulate the perception process by metabolizing exogenous molecules, including tastants and odorants. Chemosensory detection involves the interaction of chemosensory molecules with receptors. GST contributes to signal termination by metabolizing these molecules. By reducing the concentration of chemosensory molecules before receptor binding, GST modulates receptor activation and, therefore, the perception of these molecules. The balance of chemoperception by GSTs has been shown in insects as well as in mammals, although their chemosensory systems are not evolutionarily connected. This review will provide knowledge supporting the involvement of GSTs in chemoperception, describing their localization in these systems as well as their enzymatic capacity toward odorants, sapid molecules, and pheromones in insects and mammals. Their different roles in chemosensory organs will be discussed in light of the evolutionary advantage of the coupling of the detoxification system and chemosensory system through GSTs. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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Other

11 pages, 1085 KiB  
Commentary
Glutathione-S-Transferases as Potential Targets for Modulation of Nitric Oxide-Mediated Vasodilation
by Tiffany M. Russell and Des R. Richardson
Biomolecules 2022, 12(9), 1292; https://doi.org/10.3390/biom12091292 - 13 Sep 2022
Cited by 5 | Viewed by 3307
Abstract
Glutathione-S-transferases (GSTs) are highly promiscuous in terms of their interactions with multiple proteins, leading to various functions. In addition to their classical detoxification roles with multi-drug resistance-related protein-1 (MRP1), more recent studies have indicated the role of GSTs in cellular nitric [...] Read more.
Glutathione-S-transferases (GSTs) are highly promiscuous in terms of their interactions with multiple proteins, leading to various functions. In addition to their classical detoxification roles with multi-drug resistance-related protein-1 (MRP1), more recent studies have indicated the role of GSTs in cellular nitric oxide (NO) metabolism. Vasodilation is classically induced by NO through its interaction with soluble guanylate cyclase. The ability of GSTs to biotransform organic nitrates such as nitroglycerin for NO generation can markedly modulate vasodilation, with this effect being prevented by specific GST inhibitors. Recently, other structurally distinct pro-drugs that generate NO via GST-mediated catalysis have been developed as anti-cancer agents and also indicate the potential of GSTs as suitable targets for pharmaceutical development. Further studies investigating GST biochemistry could enhance our understanding of NO metabolism and lead to the generation of novel and innovative vasodilators for clinical use. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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