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Special Issue "Versatility of Glutathione Transferase Proteins"

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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 7474

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Prof. Dr. Bengt Mannervik

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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 (7 papers)

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Research

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Open AccessArticle

Inhibition Analysis and High-Resolution Crystal Structure of Mus musculus Glutathione Transferase P1-1

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

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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 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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Open AccessFeature PaperArticle

Reversibility and Low Commitment to Forward Catalysis in the Conjugation of Lipid Alkenals by Glutathione Transferase A4-4

and

Biomolecules 2023, 13(2), 329; https://doi.org/10.3390/biom13020329 - 09 Feb 2023

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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, 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 k_cat,f for ‘forward’ Michael addition to the first order k_cat,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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Open AccessArticle

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

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

Viewed by 1062

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 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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The Multifaceted Role of Glutathione S-Transferases in Health and Disease

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Biomolecules 2023, 13(4), 688; https://doi.org/10.3390/biom13040688 - 18 Apr 2023

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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 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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Open AccessReview

Compounds Inhibiting Noppera-bo, a Glutathione S-transferase Involved in Insect Ecdysteroid Biosynthesis: Novel Insect Growth Regulators

Kana Ebihara

and

Ryusuke Niwa

Biomolecules 2023, 13(3), 461; https://doi.org/10.3390/biom13030461 - 02 Mar 2023

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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, 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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Open AccessReview

Role of Insect and Mammal Glutathione Transferases in Chemoperception

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Biomolecules 2023, 13(2), 322; https://doi.org/10.3390/biom13020322 - 08 Feb 2023

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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 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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Open AccessCommentary

Glutathione-S-Transferases as Potential Targets for Modulation of Nitric Oxide-Mediated Vasodilation

Tiffany M. Russell

and

Des R. Richardson

Biomolecules 2022, 12(9), 1292; https://doi.org/10.3390/biom12091292 - 13 Sep 2022

Cited by 1 | Viewed by 1194

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 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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