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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Macromolecular Chemistry".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 58240

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Prof. Dr. Pál Perjési

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Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Pécs, Rókus Str. 2, H-7624 Pécs, Hungary
Interests: organic chemistry; medicinal chemistry; chemical biology; bioorganic chemistry; molecular toxicology; glutathione; redox homeostasis, oxidative stress; reactive oxygen species; antioxidants; chemoprevention; chalcones; flavonoids; cyclic chalcone analogs; glutathione conjugation
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Dear Colleagues,

Glutathione (γ-L-glutamyl-L-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol found in both prokaryotic and eukaryotic organisms. It plays an important role in cellular redox homeostasis, biotransformation of xenobiotics, defense against electrophilic reactive species, and control of several cellular events, among others. Most of these cellular functions are related to the thiol (SH) function of the cysteine moiety. With increasing knowledge on the molecular basis of its functions, the use of GSH as a nutritional supplement is also experiencing increasing interest. The aim of this Special Issue is to review the information gained over recent years regarding the synthesis, physicochemical characterization, and synthetic applications of GSH, as well as on the mechanism and stereochemistry of its enzyme-catalyzed and spontaneous reactions that have a role in cellular functions such as redox control, stress defense, drug biotransformation, and cell signaling. Furthermore, particular attention will also be given to the analytical methodologies used to identify and quantitate GSH conjugates and specific S-glutathionylation reactions.

Communications, full papers, and reviews on the abovementioned topics are particularly welcome.

Prof. Dr. Pál Perjési
Guest Editor

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Keywords

synthesis of GSH and GSH analogs
redox reactions of GSH
non-redox reactions of GSH
GST-catalyzed reactions
S-glutathionylation
mechanism and stereochemistry of GSH reactions
stereochemistry of GSH conjugates
biotransformation
mercapturic acid pathway

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

3 pages, 213 KiB

Open AccessEditorial

Preface to the Special Issue “Glutathione: Chemistry and Biochemistry”

by Pál Perjési

Molecules 2023, 28(16), 5993; https://doi.org/10.3390/molecules28165993 - 10 Aug 2023

Viewed by 1024

Abstract

This year we celebrate the 135th anniversary of the discovery of glutathione (L-γ-glutamyl-L-cysteinyl-glycine) [...] Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

Research

Jump to: Editorial, Review

20 pages, 7107 KiB

Open AccessArticle

New Insights on Glutathione’s Supramolecular Arrangement and Its In Silico Analysis as an Angiotensin-Converting Enzyme Inhibitor

by Antônio S. N. Aguiar, Igor D. Borges, Leonardo L. Borges, Lucas D. Dias, Ademir J. Camargo, Pál Perjesi and Hamilton B. Napolitano

Molecules 2022, 27(22), 7958; https://doi.org/10.3390/molecules27227958 - 17 Nov 2022

Cited by 3 | Viewed by 2319

Abstract

Angiotensin-converting enzyme (ACE) inhibitors are one of the most active classes for cardiovascular diseases and hypertension treatment. In this regard, developing active and non-toxic ACE inhibitors is still a continuous challenge. Furthermore, the literature survey shows that oxidative stress plays a significant role in the development of hypertension. Herein, glutathione’s molecular structure and supramolecular arrangements are evaluated as a potential ACE inhibitor. The tripeptide molecular modeling by density functional theory, the electronic structure by the frontier molecular orbitals, and the molecular electrostatic potential map to understand the biochemical processes inside the cell were analyzed. The supramolecular arrangements were studied by Hirshfeld surfaces, quantum theory of atoms in molecules, and natural bond orbital analyses. They showed distinct patterns of intermolecular interactions in each polymorph, as well as distinct stabilizations of these. Additionally, the molecular docking study presented the interactions between the active site residues of the ACE and glutathione via seven hydrogen bonds. The pharmacophore design indicated that the hydrogen bond acceptors are necessary for the interaction of this ligand with the binding site. The results provide useful information for the development of GSH analogs with higher ACE inhibitor activity. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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15 pages, 1841 KiB

Open AccessArticle

Sulodexide Increases Glutathione Synthesis and Causes Pro-Reducing Shift in Glutathione-Redox State in HUVECs Exposed to Oxygen–Glucose Deprivation: Implication for Protection of Endothelium against Ischemic Injury

by Klaudia Bontor and Bożena Gabryel

Molecules 2022, 27(17), 5465; https://doi.org/10.3390/molecules27175465 - 25 Aug 2022

Cited by 7 | Viewed by 2144

Abstract

Sulodexide (SDX), a purified glycosaminoglycan mixture used to treat vascular diseases, has been reported to exert endothelial protective effects against ischemic injury. However, the mechanisms underlying these effects remain to be fully elucidated. The emerging evidence indicated that a relatively high intracellular concentration of reduced glutathione (GSH) and a maintenance of the redox environment participate in the endothelial cell survival during ischemia. Therefore, the aim of the present study was to examine the hypothesis that SDX alleviates oxygen–glucose deprivation (OGD)-induced human umbilical endothelial cells’ (HUVECs) injury, which serves as the in vitro model of ischemia, by affecting the redox state of the GSH: glutathione disulfide (GSSG) pool. The cellular GSH, GSSG and total glutathione (tGSH) concentrations were measured by colorimetric method and the redox potential (ΔEh) of the GSSG/2GSH couple was calculated, using the Nernst equation. Furthermore, the levels of the glutamate–cysteine ligase catalytic subunit (GCLc) and the glutathione synthetase (GSS) proteins, a key enzyme for de novo GSH synthesis, were determined using enzyme-linked immunoassay (ELISA). We demonstrated that the SDX treatment in OGD conditions significantly elevated the intracellular GSH, enhanced the GSH:GSSG ratio, shifting the redox potential to a more pro-reducing status. Furthermore, SDX increased the levels of both GCLc and GSS. The results show that SDX protects the human endothelial cells against ischemic stress by affecting the GSH levels and cellular redox state. These changes suggest that the reduction in the ischemia-induced vascular endothelial cell injury through repressing apoptosis and oxidative stress associated with SDX treatment may be due to an increase in GSH synthesis and modulation of the GSH redox system. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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10 pages, 1022 KiB

Open AccessArticle

Profiling the Concentration of Reduced and Oxidized Glutathione in Rat Brain Using HPLC/DAD Chromatographic System

by George Jîtcă, Erzsébet Fogarasi, Bianca-Eugenia Ősz, Camil Eugen Vari, Ibolya Fülöp, Mircea Dumitru Croitoru, Carmen Maria Rusz and Maria Titica Dogaru

Molecules 2021, 26(21), 6590; https://doi.org/10.3390/molecules26216590 - 30 Oct 2021

Cited by 8 | Viewed by 3039

Abstract

This study aimed to develop a HPLC/DAD method in order to determine and quantify the reduced glutathione (GSH) and oxidized glutathione (GSSG) levels in rat brain. Due to the presence of the thiol group (-SH), GSH can interact with the Ellman′s reagent (DTNB), with which it forms a reaction product through which the level of GSH can be quantified, using the DAD detection system. Chromatographic separation was achieved after a derivatization process by using a mobile phase acetonitrile (A) and phosphate buffer (20 mM, pH = 2.5) (B). The compounds of interest were detected at 330 nm using a chromatographic C8 column. The method of determination met the validation criteria, specified by the regulatory bodies. The applicability of the method was demonstrated in a chronic toxicology study of central nervous system (CNS), following different treatment regimens with haloperidol. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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13 pages, 1887 KiB

Open AccessArticle

Reaction of Chalcones with Cellular Thiols. The Effect of the 4-Substitution of Chalcones and Protonation State of the Thiols on the Addition Process. Diastereoselective Thiol Addition

by Fatemeh Kenari, Szilárd Molnár and Pál Perjési

Molecules 2021, 26(14), 4332; https://doi.org/10.3390/molecules26144332 - 17 Jul 2021

Cited by 9 | Viewed by 3075

Abstract

Several biological effects of chalcones have been reported to be associated with their thiol reactivity. In vivo, the reactions can result in the formation of small-molecule or protein thiol adducts. Both types of reactions can play a role in the biological effects of this class of compounds. Progress of the reaction of 4-methyl- and 4-methoxychalcone with glutathione and N-acetylcysteine was studied by the HPLC-UV-VIS method. The reactions were conducted under three different pH conditions. HPLC-MS measurements confirmed the structure of the formed adducts. The chalcones reacted with both thiols under all incubation conditions. The initial rate and composition of the equilibrium mixtures depended on the ratio of the deprotonated form of the thiols. In the reaction of 4-methoxychalcone with N-acetylcysteine under strongly basic conditions, transformation of the kinetic adduct into the thermodynamically more stable one was observed. Addition of S-protonated N-acetylcysteine onto the polar double bonds of the chalcones showed different degrees of diastereoselectivity. Both chalcones showed a Michael-type addition reaction with the ionized and non-ionized forms of the investigated thiols. The initial reactivity of the chalcones and the equilibrium composition of the incubates showed a positive correlation with the degree of ionization of the thiols. Conversions showed systematic differences under each set of conditions. The observed differences can hint at the difference in reported biological actions of 4-methyl- and 4-methoxy-substituted chalcones. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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13 pages, 2818 KiB

Open AccessArticle

Polymerized Whey Protein Concentrate-Based Glutathione Delivery System: Physicochemical Characterization, Bioavailability and Sub-Chronic Toxicity Evaluation

by Siyu Zhang, Cuina Wang, Weigang Zhong, Alyssa H. Kemp, Mingruo Guo and Adam Killpartrick

Molecules 2021, 26(7), 1824; https://doi.org/10.3390/molecules26071824 - 24 Mar 2021

Cited by 4 | Viewed by 2501

Abstract

Glutathione (GSH) is a powerful antioxidant, but its application is limited due to poor storage stability and low bioavailability. A novel nutrient encapsulation and delivery system, consisting of polymerized whey protein concentrate and GSH, was prepared and in vivo bioavailability, antioxidant capacity and toxicity were evaluated. Polymerized whey protein concentrate encapsulated GSH (PWPC-GSH) showed a diameter of roughly 1115 ± 7.07 nm (D₅₀) and zeta potential of 30.37 ± 0.75 mV. Differential scanning calorimetry (DSC) confirmed that GSH was successfully dispersed in PWPC particles. In vivo pharmacokinetics study suggested that PWPC-GSH displayed 2.5-times and 2.6-fold enhancement in maximum concentration (C_max) and area under the concentration–time curve (AUC) as compared to free GSH. Additionally, compared with plasma of mice gavage with free GSH, significantly increased antioxidant capacity of plasma in mice with PWPC-GSH was observed (p < 0.05). Sub-chronic toxicity evaluation indicated that no adverse toxicological reactions related to oral administration of PWPC-GSH were observed on male and female rats with a diet containing PWPC-GSH up to 4% (w/w). Data indicated that PWPC may be an effective carrier for GSH to improve bioavailability and antioxidant capacity. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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12 pages, 739 KiB

Open AccessArticle

Genetic Polymorphism of GSTP-1 Affects Cyclophosphamide Treatment of Autoimmune Diseases

by Péter Hajdinák, Melinda Szabó, Emese Kiss, Lili Veress, Lívius Wunderlich and András Szarka

Molecules 2020, 25(7), 1542; https://doi.org/10.3390/molecules25071542 - 28 Mar 2020

Cited by 13 | Viewed by 4536

Abstract

Cyclophosphamide is one of the most potent and reliable anti-cancer and immunosuppressive drugs. In our study, 33 individuals with different autoimmune diseases were treated with cyclophosphamide according to standard protocols. The responses to the treatments were determined by measuring the alteration of several typical parameters characterizing the given autoimmune diseases over time. We concluded that about 45% of the patients responded to the treatment. Patients were genotyped for polymorphisms of the CYP3A4, CYP2B6, GSTM1, GSTT1, and GSTP1 genes and disease remission cases were compared to the individual polymorphic genotypes. It was found that the GSTP1 I105V allelic variation significantly associated with the cyclophosphamide treatment-dependent disease-remissions. At the same time the GSH content of the erythrocytes in the patients with I105V allelic variation did not change. It appears that the individuals carrying the Ile105Val SNP in at least one copy had a significantly higher response rate to the treatment. Since this variant of GSTP1 can be characterized by lower conjugation capacity that results in an elongated and higher therapeutic dose of cyclophosphamide, our data suggest that the decreased activity of this variant of GSTP1 can be in the background of the more effective disease treatment. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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Review

Jump to: Editorial, Research

22 pages, 1187 KiB

Open AccessReview

Glutathione-Related Enzymes and Proteins: A Review

by Janka Vašková, Ladislav Kočan, Ladislav Vaško and Pál Perjési

Molecules 2023, 28(3), 1447; https://doi.org/10.3390/molecules28031447 - 2 Feb 2023

Cited by 76 | Viewed by 8397

Abstract

The tripeptide glutathione is found in all eukaryotic cells, and due to the compartmentalization of biochemical processes, its synthesis takes place exclusively in the cytosol. At the same time, its functions depend on its transport to/from organelles and interorgan transport, in which the liver plays a central role. Glutathione is determined as a marker of the redox state in many diseases, aging processes, and cell death resulting from its properties and reactivity. It also uses other enzymes and proteins, which enables it to engage and regulate various cell functions. This paper approximates the role of these systems in redox and detoxification reactions such as conjugation reactions of glutathione-S-transferases, glyoxylases, reduction of peroxides through thiol peroxidases (glutathione peroxidases, peroxiredoxins) and thiol–disulfide exchange reactions catalyzed by glutaredoxins. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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29 pages, 5875 KiB

Open AccessReview

Glutathione-Mediated Conjugation of Anticancer Drugs: An Overview of Reaction Mechanisms and Biological Significance for Drug Detoxification and Bioactivation

by Agnieszka Potęga

Molecules 2022, 27(16), 5252; https://doi.org/10.3390/molecules27165252 - 17 Aug 2022

Cited by 40 | Viewed by 8057

Abstract

The effectiveness of many anticancer drugs depends on the creation of specific metabolites that may alter their therapeutic or toxic properties. One significant route of biotransformation is a conjugation of electrophilic compounds with reduced glutathione, which can be non-enzymatic and/or catalyzed by glutathione-dependent enzymes. Glutathione usually combines with anticancer drugs and/or their metabolites to form more polar and water-soluble glutathione S-conjugates, readily excreted outside the body. In this regard, glutathione plays a role in detoxification, decreasing the likelihood that a xenobiotic will react with cellular targets. However, some drugs once transformed into thioethers are more active or toxic than the parent compound. Thus, glutathione conjugation may also lead to pharmacological or toxicological effects through bioactivation reactions. My purpose here is to provide a broad overview of the mechanisms of glutathione-mediated conjugation of anticancer drugs. Additionally, I discuss the biological importance of glutathione conjugation to anticancer drug detoxification and bioactivation pathways. I also consider the potential role of glutathione in the metabolism of unsymmetrical bisacridines, a novel prosperous class of anticancer compounds developed in our laboratory. The knowledge on glutathione-mediated conjugation of anticancer drugs presented in this review may be noteworthy for improving cancer therapy and preventing drug resistance in cancers. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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20 pages, 1835 KiB

Open AccessReview

Detection of Oxidative Stress Induced by Nanomaterials in Cells—The Roles of Reactive Oxygen Species and Glutathione

by Jan Čapek and Tomáš Roušar

Molecules 2021, 26(16), 4710; https://doi.org/10.3390/molecules26164710 - 4 Aug 2021

Cited by 52 | Viewed by 8391

Abstract

The potential of nanomaterials use is huge, especially in fields such as medicine or industry. Due to widespread use of nanomaterials, their cytotoxicity and involvement in cellular pathways ought to be evaluated in detail. Nanomaterials can induce the production of a number of substances in cells, including reactive oxygen species (ROS), participating in physiological and pathological cellular processes. These highly reactive substances include: superoxide, singlet oxygen, hydroxyl radical, and hydrogen peroxide. For overall assessment, there are a number of fluorescent probes in particular that are very specific and selective for given ROS. In addition, due to the involvement of ROS in a number of cellular signaling pathways, understanding the principle of ROS production induced by nanomaterials is very important. For defense, the cells have a number of reparative and especially antioxidant mechanisms. One of the most potent antioxidants is a tripeptide glutathione. Thus, the glutathione depletion can be a characteristic manifestation of harmful effects caused by the prooxidative-acting of nanomaterials in cells. For these reasons, here we would like to provide a review on the current knowledge of ROS-mediated cellular nanotoxicity manifesting as glutathione depletion, including an overview of approaches for the detection of ROS levels in cells. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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19 pages, 854 KiB

Open AccessReview

Glutathione in Protein Redox Modulation through S-Glutathionylation and S-Nitrosylation

by Elena Kalinina and Maria Novichkova

Molecules 2021, 26(2), 435; https://doi.org/10.3390/molecules26020435 - 15 Jan 2021

Cited by 61 | Viewed by 6324

Abstract

S-glutathionylation and S-nitrosylation are reversible post-translational modifications on the cysteine thiol groups of proteins, which occur in cells under physiological conditions and oxidative/nitrosative stress both spontaneously and enzymatically. They are important for the regulation of the functional activity of proteins and intracellular processes. Connecting link and “switch” functions between S-glutathionylation and S-nitrosylation may be performed by GSNO, the generation of which depends on the GSH content, the GSH/GSSG ratio, and the cellular redox state. An important role in the regulation of these processes is played by Trx family enzymes (Trx, Grx, PDI), the activity of which is determined by the cellular redox status and depends on the GSH/GSSG ratio. In this review, we analyze data concerning the role of GSH/GSSG in the modulation of S-glutathionylation and S-nitrosylation and their relationship for the maintenance of cell viability. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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26 pages, 4119 KiB

Open AccessReview

Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism—Review

by Trnka Daniel, Hossain Md Faruq, Jordt Laura Magdalena, Gellert Manuela and Lillig Christopher Horst

Molecules 2020, 25(17), 3860; https://doi.org/10.3390/molecules25173860 - 25 Aug 2020

Cited by 21 | Viewed by 5393

Abstract

Glutathione (GSH) was initially identified and characterized for its redox properties and later for its contributions to detoxification reactions. Over the past decade, however, the essential contributions of glutathione to cellular iron metabolism have come more and more into focus. GSH is indispensable in mitochondrial iron-sulfur (FeS) cluster biosynthesis, primarily by co-ligating FeS clusters as a cofactor of the CGFS-type (class II) glutaredoxins (Grxs). GSH is required for the export of the yet to be defined FeS precursor from the mitochondria to the cytosol. In the cytosol, it is an essential cofactor, again of the multi-domain CGFS-type Grxs, master players in cellular iron and FeS trafficking. In this review, we summarize the recent advances and progress in this field. The most urgent open questions are discussed, such as the role of GSH in the export of FeS precursors from mitochondria, the physiological roles of the CGFS-type Grx interactions with BolA-like proteins and the cluster transfer between Grxs and recipient proteins. Full article

(This article belongs to the Special Issue Glutathione: Chemistry and Biochemistry)

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