Glutathione and GSH-Related Enzymes in the Oxidative and Reductive Stresses

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (20 September 2023) | Viewed by 5853

Special Issue Editors

Department of Plant Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
Interests: oxidative stress; plant antioxidant mechanisms; redox homeostasis; redox regulation; glutathione; glutathione transferases; glutathione peroxidases; salicylic acid; tomato transformation; application of CRISPR/Cas method
Department of Plant Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
Interests: glutathione; glutathione transferases; osmotic stress; oxidative stress; reactive oxygen species; redox homeostasis; salinity; stress response of tomato cultivars

Special Issue Information

Dear Colleagues,

The traditional view that reactive oxygen species (ROS) are considered damaging compounds of cells has now shifted toward ROS being an integrative part of signaling. The interaction between ROS, enzymatic, and non-enzymatic antioxidants comprises the cellular redox state. Recent evidence suggests that over-accumulation of reductants can cause “reductive stress”, which may also increase ROS levels. Considering that redox processes are not spontaneous in cells, but the adequate reaction velocity and appropriate specificity are achieved by the catalyzing activity of enzymes, glutathione-utilizing enzymes have attracted special attention. Glutathione is the central player of redox reactions that are fundamental metabolic processes through which cells convert and distribute the energy that is necessary for growth and development, even in the presence of unfavorable environmental factors.

As guest editors, we invite you to contribute to this Special Issue, whose focus will be the role of glutathione and related enzymes in the occurrence or regulation of oxidative and/or reductive stresses. We invite articles from researchers in a wide range of fields, such as physiology, biochemistry, and molecular biology related to the function or changed expression of very diverse redox-related enzymes.

Dr. Jolán Csiszár
Dr. Edit Horváth
Guest Editors

Manuscript Submission Information

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Keywords

  • antioxidant enzymes
  • glutaredoxin
  • glutathione
  • glutathione peroxidase
  • glutathione reductase
  • glutathione transferase
  • oxidative stress
  • reactive oxygen species
  • reductive stress
  • redox regulation

Published Papers (4 papers)

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Research

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12 pages, 3589 KiB  
Article
Repurposing Glutathione Transferases: Directed Evolution Combined with Chemical Modification for the Creation of a Semisynthetic Enzyme with High Hydroperoxidase Activity
by Irene Axarli, Farid Ataya and Nikolaos E. Labrou
Antioxidants 2024, 13(1), 41; https://doi.org/10.3390/antiox13010041 - 25 Dec 2023
Viewed by 1224
Abstract
Glutathione peroxidases (GPXs) are antioxidant selenoenzymes, which catalyze the reduction of hydroperoxides via glutathione (GSH), providing protection to cells against oxidative stress metabolites. The present study aims to create an efficient semisynthetic GPX based on the scaffold of tau class glutathione transferase (GSTU). [...] Read more.
Glutathione peroxidases (GPXs) are antioxidant selenoenzymes, which catalyze the reduction of hydroperoxides via glutathione (GSH), providing protection to cells against oxidative stress metabolites. The present study aims to create an efficient semisynthetic GPX based on the scaffold of tau class glutathione transferase (GSTU). A library of GSTs was constructed via DNA shuffling, using three homologue GSTUs from Glycine max as parent sequences. The DNA library of the shuffled genes was expressed in E. coli and the catalytic activity of the shuffled enzymes was screened using cumene hydroperoxide (CuOOH) as substrate. A chimeric enzyme variant (named Sh14) with 4-fold enhanced GPX activity, compared to the wild-type enzyme, was identified and selected for further study. Selenocysteine (Sec) was substituted for the active-site Ser13 residue of the Sh14 variant via chemical modification. The GPX activity (kcat) and the specificity constant (kcatm) of the evolved seleno-Sh14 enzyme (SeSh14) was increased 177- and 2746-fold, respectively, compared to that of the wild-type enzyme for CuOOH. Furthermore, SeSh14 effectively catalyzed the reduction of hydrogen peroxide, an activity that is completely undetectable in all GSTs. Such an engineered GPX-like biocatalyst based on the GSTU scaffold might serve as a catalytic bioscavenger for the detoxification of hazardous hydroperoxides. Furthermore, our results shed light on the evolution of GPXs and their structural and functional link with GSTs. Full article
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20 pages, 4965 KiB  
Article
Glutathione Transferases Are Involved in the Genotype-Specific Salt-Stress Response of Tomato Plants
by Edit Horváth, Kitti Kulman, Bernát Tompa, Ádám Barnabás Hajnal, Alina Pelsőczi, Krisztina Bela, Ágnes Gallé and Jolán Csiszár
Antioxidants 2023, 12(9), 1682; https://doi.org/10.3390/antiox12091682 - 28 Aug 2023
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Abstract
Glutathione transferases (GSTs) are one of the most versatile multigenic enzyme superfamilies. In our experiments, the involvement of the genotype-specific induction of GST genes and glutathione- or redox-related genes in pathways regulating salt-stress tolerance was examined in tomato cultivars (Solanum lycopersicum Moneymaker, [...] Read more.
Glutathione transferases (GSTs) are one of the most versatile multigenic enzyme superfamilies. In our experiments, the involvement of the genotype-specific induction of GST genes and glutathione- or redox-related genes in pathways regulating salt-stress tolerance was examined in tomato cultivars (Solanum lycopersicum Moneymaker, Mobil, and Elán F1). The growth of the Mobil plants was adversely affected during salt stress (100 mM of NaCl), which might be the result of lowered glutathione and ascorbate levels, a more positive glutathione redox potential (EGSH), and reduced glutathione reductase (GR) and GST activities. In contrast, the Moneymaker and Elán F1 cultivars were able to restore their growth and exhibited higher GR and inducible GST activities, as well as elevated, non-enzymatic antioxidant levels, indicating their enhanced salt tolerance. Furthermore, the expression patterns of GR, selected GST, and transcription factor genes differed significantly among the three cultivars, highlighting the distinct regulatory mechanisms of the tomato genotypes during salt stress. The correlations between EGSH and gene expression data revealed several robust, cultivar-specific associations, underscoring the complexity of the stress response mechanism in tomatoes. Our results support the cultivar-specific roles of distinct GST genes during the salt-stress response, which, along with WRKY3, WRKY72, DREB1, and DREB2, are important players in shaping the redox status and the development of a more efficient stress tolerance in tomatoes. Full article
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18 pages, 3342 KiB  
Article
Functional Analysis of GSTK1 in Peroxisomal Redox Homeostasis in HEK-293 Cells
by Cláudio F. Costa, Celien Lismont, Serhii Chornyi, Hongli Li, Mohamed A. F. Hussein, Hans R. Waterham and Marc Fransen
Antioxidants 2023, 12(6), 1236; https://doi.org/10.3390/antiox12061236 - 07 Jun 2023
Cited by 3 | Viewed by 1673
Abstract
Peroxisomes serve as important centers for cellular redox metabolism and communication. However, fundamental gaps remain in our understanding of how the peroxisomal redox equilibrium is maintained. In particular, very little is known about the function of the nonenzymatic antioxidant glutathione in the peroxisome [...] Read more.
Peroxisomes serve as important centers for cellular redox metabolism and communication. However, fundamental gaps remain in our understanding of how the peroxisomal redox equilibrium is maintained. In particular, very little is known about the function of the nonenzymatic antioxidant glutathione in the peroxisome interior and how the glutathione antioxidant system balances with peroxisomal protein thiols. So far, only one human peroxisomal glutathione-consuming enzyme has been identified: glutathione S-transferase 1 kappa (GSTK1). To study the role of this enzyme in peroxisomal glutathione regulation and function, a GSTK1-deficient HEK-293 cell line was generated and fluorescent redox sensors were used to monitor the intraperoxisomal GSSG/GSH and NAD+/NADH redox couples and NADPH levels. We provide evidence that ablation of GSTK1 does not change the basal intraperoxisomal redox state but significantly extends the recovery period of the peroxisomal glutathione redox sensor po-roGFP2 upon treatment of the cells with thiol-specific oxidants. Given that this delay (i) can be rescued by reintroduction of GSTK1, but not its S16A active site mutant, and (ii) is not observed with a glutaredoxin-tagged version of po-roGFP2, our findings demonstrate that GSTK1 contains GSH-dependent disulfide bond oxidoreductase activity. Full article
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Review

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29 pages, 10135 KiB  
Review
Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications
by Ning Lv, Chunyan Huang, Haoyan Huang, Zhiqiang Dong, Xijing Chen, Chengcan Lu and Yongjie Zhang
Antioxidants 2023, 12(11), 1970; https://doi.org/10.3390/antiox12111970 - 06 Nov 2023
Cited by 2 | Viewed by 1300
Abstract
Glutathione S-transferases (GSTs) are a major class of phase II metabolic enzymes. Besides their essential role in detoxification, GSTs also exert diverse biological activities in the occurrence and development of various diseases. In the past few decades, much research interest has been paid [...] Read more.
Glutathione S-transferases (GSTs) are a major class of phase II metabolic enzymes. Besides their essential role in detoxification, GSTs also exert diverse biological activities in the occurrence and development of various diseases. In the past few decades, much research interest has been paid to exploring the mechanisms of GST overexpression in tumor drug resistance. Correspondingly, many GST inhibitors have been developed and applied, solely or in combination with chemotherapeutic drugs, for the treatment of multi-drug resistant tumors. Moreover, novel roles of GSTs in other diseases, such as pulmonary fibrosis and neurodegenerative diseases, have been recognized in recent years, although the exact regulatory mechanisms remain to be elucidated. This review, firstly summarizes the roles of GSTs and their overexpression in the above-mentioned diseases with emphasis on the modulation of cell signaling pathways and protein functions. Secondly, specific GST inhibitors currently in pre-clinical development and in clinical stages are inventoried. Lastly, applications of GST inhibitors in targeting cell signaling pathways and intracellular biological processes are discussed, and the potential for disease treatment is prospected. Taken together, this review is expected to provide new insights into the interconnection between GST overexpression and human diseases, which may assist future drug discovery targeting GSTs. Full article
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