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Glutathione. (A) Structure of glutathione (GSH) and pK a values for chemical systems. The pK a of the GSH thiol is lower in the intracellular environment. (B) Glutathione synthesis and distribution through the blood circulation as a source of cysteine. (C) Calculation of the redox potential for glutathione-containing buffers using the Nernst equation. The y-axis depicts the ratio of GSH:GSSG in the redox buffer system. The effects of pH on the redox potential are plotted for pH 7.0, 7.4, and 8.0 and demonstrate that increasing the pH lowers the redox potential of the GSH:GSSG buffer. Glutathione redox buffers are useful tools to investigate redox-sensitive proteins. Redox potentials for thioredoxin, glutaredoxin, glutathione, and NADPH under standard conditions are listed. (D) Biological functions of glutathione. cGCS, c-glutamylcysteine ligase; DP, dipeptidases; GGT, c-glutamyl transferase; GS, GSH synthase; NADPH, nicotinamide adenine dinucleotide phosphate. Color images are available online.
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Over the past several years, oxidative post-translational modifications of protein cysteines have been recognized for their critical roles in physiology and pathophysiology. Cells have harnessed thiol modifications involving both oxidative and reductive steps for signaling and protein processing. One of these stages requires oxidation...
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... 1888, De Rey-Pailhade originally described ''philothion,'' which Hopkins rediscovered in 1921 and renamed as glutathione (GSH) (8). GSH is a small tripeptide comprising glutamine, cysteine, and glycine (c-l-glutamyl-lcysteinylglycine) (Fig. 3A). Every cell synthesizes GSH in a two-step process catalyzed by glutamate-cysteine ligase (previously known as c-glutamylcysteine synthase) and GSH synthetase in the cytoplasm (Fig. 3B). The unusual peptide bond between the c-glutamyl side chain and cysteine protects GSH from breakdown by cellular and circulating serum peptidases (111). ...
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... rediscovered in 1921 and renamed as glutathione (GSH) (8). GSH is a small tripeptide comprising glutamine, cysteine, and glycine (c-l-glutamyl-lcysteinylglycine) (Fig. 3A). Every cell synthesizes GSH in a two-step process catalyzed by glutamate-cysteine ligase (previously known as c-glutamylcysteine synthase) and GSH synthetase in the cytoplasm (Fig. 3B). The unusual peptide bond between the c-glutamyl side chain and cysteine protects GSH from breakdown by cellular and circulating serum peptidases (111). The estimated pK a of the thiol in the cellular environment is between 8.5 and 8.7 (68, 148), which confers low reactivity and poor antioxidant properties to GSH. However, due to the ...
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... reticulum (ER), which contains the enzymatic machinery to catalyze protein disulfide formation, has a more oxidizing environment of -180 mV, established by a lower GSH:GSSG ratio. The Nernst equation allows researchers to calculate the redox potential and recreate redox buffers with defined redox potential to mimic physiological conditions (159) (Fig. ...
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... normal GSH turnover is about 40 mmol per day in a human adult and is estimated to be slightly higher than the protein cysteine turnover (168). All functions of glutathione are summarized in Figure 3D. ...
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... 1888, De Rey-Pailhade originally described ''philothion,'' which Hopkins rediscovered in 1921 and renamed as glutathione (GSH) (8). GSH is a small tripeptide comprising glutamine, cysteine, and glycine (c-l-glutamyl-lcysteinylglycine) (Fig. 3A). Every cell synthesizes GSH in a two-step process catalyzed by glutamate-cysteine ligase (previously known as c-glutamylcysteine synthase) and GSH synthetase in the cytoplasm (Fig. 3B). The unusual peptide bond between the c-glutamyl side chain and cysteine protects GSH from breakdown by cellular and circulating serum peptidases (111). ...
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... rediscovered in 1921 and renamed as glutathione (GSH) (8). GSH is a small tripeptide comprising glutamine, cysteine, and glycine (c-l-glutamyl-lcysteinylglycine) (Fig. 3A). Every cell synthesizes GSH in a two-step process catalyzed by glutamate-cysteine ligase (previously known as c-glutamylcysteine synthase) and GSH synthetase in the cytoplasm (Fig. 3B). The unusual peptide bond between the c-glutamyl side chain and cysteine protects GSH from breakdown by cellular and circulating serum peptidases (111). The estimated pK a of the thiol in the cellular environment is between 8.5 and 8.7 (68, 148), which confers low reactivity and poor antioxidant properties to GSH. However, due to the ...
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... reticulum (ER), which contains the enzymatic machinery to catalyze protein disulfide formation, has a more oxidizing environment of -180 mV, established by a lower GSH:GSSG ratio. The Nernst equation allows researchers to calculate the redox potential and recreate redox buffers with defined redox potential to mimic physiological conditions (159) (Fig. ...
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The ocular lens has a very high content of the antioxidant glutathione (GSH) and the enzymes that can recycle its oxidized form, glutathione disulfide (GSSG), for further use. It can be synthesized in the lens and, in part, transported from the neighboring anterior aqueous humor and posterior vitreous body. GSH is known to protect the thiols of the...
Citations
... An alternative mechanism involves the initial oxidative modification of a reduced protein thiol (e.g., thiyl radical -S•, sulfenic acid -SOH, S-nitrosylation product -SNO), which can subsequently react with a reduced glutathione (GSH) molecule [56]. This can occur through enzymatic reactions catalysed by Glutathione S-transferase pi (GSTP) or Glutaredoxins (Grx) [60][61][62]. Several reports have also established a role for Cys-rich proteins, such as Thioredoxin (Trx), Srx and Grx in the reversal glutathionylation process (deglutathionylation) [63][64][65], with Grx catalysing both the forward and reverse reactions of S-glutathionylation [62,63,66] and GSTP potentiating S-glutathionylation reactions in response to oxidative and nitrosative stress [60]. ...
Oxidation–reduction post-translational modifications (redox-PTMs) are chemical alterations to amino acids of proteins. Redox-PTMs participate in the regulation of protein conformation, localization and function, acting as signalling effectors that impact many essential biochemical processes in the cells. Crucially, the dysregulation of redox-PTMs of proteins has been implicated in the pathophysiology of numerous human diseases, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This review aims to highlight the current gaps in knowledge in the field of redox-PTMs biology and to explore new methodological advances in proteomics and computational modelling that will pave the way for a better understanding of the role and therapeutic potential of redox-PTMs of proteins in neurodegenerative diseases. Here, we summarize the main types of redox-PTMs of proteins while providing examples of their occurrence in neurodegenerative diseases and an overview of the state-of-the-art methods used for their detection. We explore the potential of novel computational modelling approaches as essential tools to obtain insights into the precise role of redox-PTMs in regulating protein structure and function. We also discuss the complex crosstalk between various PTMs that occur in living cells. Finally, we argue that redox-PTMs of proteins could be used in the future as diagnosis and prognosis biomarkers for neurodegenerative diseases.
... The application of MS has become one of the leading platforms for profiling redox post-transcriptional modifications on a large scale [175]. ...
... In MS analysis, switch assays are particularly useful when the modification is chemically labile and unlikely to survive sample preparation [175]. ...
Antioxidant defenses in biological systems ensure redox homeostasis, regulating baseline levels of reactive oxygen and nitrogen species (ROS and RNS). Oxidative stress (OS), characterized by a lack of antioxidant defenses or an elevation in ROS and RNS, may cause a modification of biomolecules, ROS being primarily absorbed by proteins. As a result of both genome and environment interactions, proteomics provides complete information about a cell’s proteome, which changes continuously. Besides measuring protein expression levels, proteomics can also be used to identify protein modifications, localizations, the effects of added agents, and the interactions between proteins. Several oxidative processes are frequently used to modify proteins post-translationally, including carbonylation, oxidation of amino acid side chains, glycation, or lipid peroxidation, which produces highly reactive alkenals. Reactive alkenals, such as 4-hydroxy-2-nonenal, are added to cysteine (Cys), lysine (Lys), or histidine (His) residues by a Michael addition, and tyrosine (Tyr) residues are nitrated and Cys residues are nitrosylated by a Michael addition. Oxidative and nitrosative stress have been implicated in many neurodegenerative diseases as a result of oxidative damage to the brain, which may be especially vulnerable due to the large consumption of dioxygen. Therefore, the current methods applied for the detection, identification, and quantification in redox proteomics are of great interest. This review describes the main protein modifications classified as chemical reactions. Finally, we discuss the importance of redox proteomics to health and describe the analytical methods used in redox proteomics.
... In the context of Grx1 activity, it should be mentioned that silencing of the GRX1 gene caused a significant change in GSH/GSSG ratio, leading to ROS hyperaccumulation; in turn, overexpression of GRX1 reduced cellular ROS levels [29]. In addition, GRX1 knockdown increased the S-glutathionylation of DJ-1 and HSP60 proteins, leading to a decrease in mitochondrial respiratory capacity and ATP production. ...
Glutaredoxin 1 (Grx1) is an essential enzyme that regulates redox signal transduction and repairs protein oxidation by reversing S-glutathionylation, an oxidative modification of protein cysteine residues. Grx1 removes glutathione from proteins to restore their reduced state (protein-SH) and regulate protein-SSG levels in redox signaling networks. Thus, it can exert an influence on the development of cancer. To further investigate this problem, we performed an analysis of Grx1 expression in colon adenocarcinoma samples from the Polish population of patients with primary colon adenocarcinoma (stages I and II of colon cancer) and those with regional lymph node metastasis (stage III of colon cancer). Our study revealed a significant correlation between the expression of Grx1 protein through immunohistochemical analysis and various clinical characteristics of patients, such as histological grade, depth of invasion, angioinvasion, staging, regional lymph node invasion, and PCNA expression. It was found that almost 88% of patients with stage I had high levels of Grx1 expression, while only 1% of patients with stage III exhibited high levels of Grx1 protein expression. Furthermore, the study discovered that high levels of Grx1 expression were present in samples of colon mucosa without any pathological changes. These results were supported by in vitro analysis conducted on colorectal cancer cell lines that corresponded to stages I, II, and III of colorectal cancer, using qRT-PCR and Western blot.
... Instead, following the onset of severe oxidative stress condition, part of GSH is used to eliminate free radicals, thus leading to a reduction in GSH concentration and an increase of GSSG level. The decrease of GSH/GSSG ratio produces a large spectrum of oxidized biological molecules and overwhelms protein S-glutathionylation (mainly through the above-mentioned thiol-disulfide exchange reaction (2)) trying to prevent the redox signaling disruption [35]. S-glutathionylation can occur spontaneously in a oxidized environment or can be catalyzed by enzymatic systems, such as glutathione S-transferase (GST), peroxiredoxins and sometimes glutaredoxins, able to transfer glutathione molecule to targeted proteins [35]. ...
... The decrease of GSH/GSSG ratio produces a large spectrum of oxidized biological molecules and overwhelms protein S-glutathionylation (mainly through the above-mentioned thiol-disulfide exchange reaction (2)) trying to prevent the redox signaling disruption [35]. S-glutathionylation can occur spontaneously in a oxidized environment or can be catalyzed by enzymatic systems, such as glutathione S-transferase (GST), peroxiredoxins and sometimes glutaredoxins, able to transfer glutathione molecule to targeted proteins [35]. In particular, among the different cytosolic GST, it has been reported that GSTπ, mainly present in the lung and liver but also in the brain and heart, induces both in vitro and in vivo S-glutathionylation [36,37]. ...
... In particular, thioredoxin, glutaredoxin and protein disulfide isomerase, belonging to the protein thiol-disulfide oxidoreductase family, represent pivotal enzymes able to catalyze protein disulfide bond reduction. Given that they can occasionally also induce S-glutathionylation under oxidative stress condition, as reported above, these enzymes contribute to the creation of a highly dynamic redox microenvironment [35]. Thioredoxin is involved in pro-proliferative, anti-apoptotic and anti-oxidative mechanisms, and its glutathionylation causes an impairment of its function [40]. ...
Hemoglobin is one of the proteins that are more susceptible to S-glutathionylation and the levels of its modified form, glutathionyl hemoglobin (HbSSG), increase in several human pathological conditions. The scope of the present review is to provide knowledge about how hemoglobin is subjected to S-glutathionylation and how this modification affects its functionality. The different diseases that showed increased levels of HbSSG and the methods used for its quantification in clinical investigations will be also outlined. Since there is a growing need for precise and reliable methods for markers of oxidative stress in human blood, this review highlights how HbSSG is emerging more and more as a good indicator of severe oxidative stress but also as a key pathogenic factor in several diseases.
... This system comprises antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, which scavenge and neutralise ROS. Additionally, non-enzymatic antioxidants, including vitamin C, vitamin E, and glutathione, play essential roles in maintaining cellular redox balance [219][220][221][222][223][224]. In this line, mitochondrial dysfunction, which implies an inability to overcome this oxidative stress, has been implicated in various diseases, including neurodegenerative disorders. ...
Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.
... Peroxiredoxin and thioredoxin (which is needed to recycle peroxiredoxin) detoxify mainly lipid peroxides in the membrane [31], and play a fundamental role in RBC redox homeostasis in vivo [32]. Glutaredoxins are responsible for keeping thiols in a reduced state; they were isolated from RBCs almost 30 years ago, but their role is still elusive [33,34]. ...
Beyond their established role as oxygen carriers, red blood cells have recently been found to contribute to systemic NO and sulfide metabolism and act as potent circulating antioxidant cells. Emerging evidence indicates that reactive species derived from the metabolism of O2, NO, and H2S can interact with each other, potentially influencing common biological targets. These interactions have been encompassed in the concept of the reactive species interactome. This review explores the potential application of the concept of reactive species interactome to understand the redox physiology of RBCs. It specifically examines how reactive species are generated and detoxified, their interactions with each other, and their targets. Hemoglobin is a key player in the reactive species interactome within RBCs, given its abundance and fundamental role in O2/CO2 exchange, NO transport/metabolism, and sulfur species binding/production. Future research should focus on understanding how modulation of the reactive species interactome may regulate RBC biology, physiology, and their systemic effects.
... The authors measured the levels of malondialdehyde (MDA), extracellular SOD, total antioxidant capacity and ROS in lung tissue and of NF-kB-mediated inflammatory genes expression of TNF-alpha, IL-1 beta and IL-6 in these animal models [109,110]. Second, glutaredoxin, an enzyme involved in redox signaling, reverses a post-translational modification known as protein S-glutathiolation and restores cysteine residues on target proteins [111,112]. Recently, it was shown that mice deficient in the glutaredoxin gene (GLRX) show excessive collagen deposition following either treatment with bleomycin or recombinant TGF beta-1. Further, transgenic mice that conditionally overexpress GLRX suppressed TGF beta-1-induced lung fibrosis [113]. ...
Lung fibrosis is a progressive fatal disease in which deregulated wound healing of lung epithelial cells drives progressive fibrotic changes. Persistent lung injury due to oxidative stress and chronic inflammation are central features of lung fibrosis. Chronic cigarette smoking causes oxidative stress and is a major risk factor for lung fibrosis. The objective of this manuscript is to develop an adverse outcome pathway (AOP) that serves as a framework for investigation of the mechanisms of lung fibrosis due to lung injury caused by inhaled toxicants, including cigarette smoke. Based on the weight of evidence, oxidative stress is proposed as a molecular initiating event (MIE) which leads to increased secretion of proinflammatory and profibrotic mediators (key event 1 (KE1)). At the cellular level, these proinflammatory signals induce the recruitment of inflammatory cells (KE2), which in turn, increase fibroblast proliferation and myofibroblast differentiation (KE3). At the tissue level, an increase in extracellular matrix deposition (KE4) subsequently culminates in lung fibrosis, the adverse outcome. We have also defined a new KE relationship between the MIE and KE3. This AOP provides a mechanistic platform to understand and evaluate how persistent oxidative stress from lung injury may develop into lung fibrosis.
... As mentioned above, S-glutathionylation of proteins is dynamic and reversible, so the steady-state level of protein-SSG under various conditions depends on the relative rates of glutathionylation (formation) and deglutathionylation (breakdown) (Figure 3), providing another level of regulation for cellular processes [53]. Specific binding sites for glutathione have been characterized on glutaredoxin, which is understood to be the primary catalyst of deglutathionylation [54]. As noted, glutaredoxin belongs to the thioredoxin superfamily of enzymes, which includes thioredoxins, glutathione peroxidases, glutathione S-transferases, and protein disulfide isomerases (PDI) [55]. ...
... As noted, glutaredoxin belongs to the thioredoxin superfamily of enzymes, which includes thioredoxins, glutathione peroxidases, glutathione S-transferases, and protein disulfide isomerases (PDI) [55]. Structurally, all of these proteins display a thioredoxin-fold motif, which is essential for their redox function; however, they otherwise possess only low sequence similarity [54]. ...
... As mentioned above, S-glutathionylation of proteins is dynamic and reversible the steady-state level of protein-SSG under various conditions depends on the rela rates of glutathionylation (formation) and deglutathionylation (breakdown) (Figure providing another level of regulation for cellular processes [53]. Specific binding sites glutathione have been characterized on glutaredoxin, which is understood to be the mary catalyst of deglutathionylation [54]. As noted, glutaredoxin belongs to the thio doxin superfamily of enzymes, which includes thioredoxins, glutathione peroxida glutathione S-transferases, and protein disulfide isomerases (PDI) [55]. ...
This Special Issue of Antioxidants on Glutathione (GSH) and Glutaredoxin (Grx) was designed to collect review articles and original research studies focused on advancing the current understanding of the roles of the GSH/Grx system in cellular homeostasis and disease processes. The tripeptide glutathione (GSH) is the most abundant non-enzymatic antioxidant/nucleophilic molecule in cells. In addition to various metabolic reactions involving GSH and its oxidized counterpart GSSG, oxidative post-translational modification (PTM) of proteins has been a focal point of keen interest in the redox field over the last few decades. In particular, the S-glutathionylation of proteins (protein-SSG formation), i.e., mixed disulfides between GSH and protein thiols, has been studied extensively. This reversible PTM can act as a regulatory switch to interconvert inactive and active forms of proteins, thereby mediating cell signaling and redox homeostasis. The unique architecture of the GSH molecule enhances its relative abundance in cells and contributes to the glutathionyl specificity of the primary catalytic activity of the glutaredoxin enzymes, which play central roles in redox homeostasis and signaling, and in iron metabolism in eukaryotes and prokaryotes under physiological and pathophysiological conditions. The class-1 glutaredoxins are characterized as cytosolic GSH-dependent oxidoreductases that catalyze reversible protein S-glutathionylation specifically, thereby contributing to the regulation of redox signal transduction and/or the protection of protein thiols from irreversible oxidation. This Special Issue includes nine other articles: three original studies and six review papers. Together, these ten articles support the central theme that GSH/Grx is a unique system for regulating thiol-redox hemostasis and redox-signal transduction, and the dysregulation of the GSH/Grx system is implicated in the onset and progression of various diseases involving oxidative stress. Within this context, it is important to appreciate the complementary functions of the GSH/Grx and thioredoxin systems not only in thiol-disulfide regulation but also in reversible S-nitrosylation. Several potential clinical applications have emerged from a thorough understanding of the GSH/Grx redox regulatory system at the molecular level, and in various cell types in vitro and in vivo, including, among others, the concept that elevating Grx content/activity could serve as an anti-fibrotic intervention; and discovering small molecules that mimic the inhibitory effects of S-glutathionylation on dimer association could identify novel anti-viral agents that impact the key protease activities of the HIV and SARS-CoV-2 viruses. Thus, this Special Issue on Glutathione and Glutaredoxin has focused attention and advanced understanding of an important aspect of redox biology, as well as spawning questions worthy of future study.
... S-glutathionylation is an oxidative PTM with a dynamic and reversible process, acting as a redox "switch" and playing an important role in protein function, interaction, and localization [14]. Under oxidative stress, the exposed and deprotonated active cysteines can covalent with plentiful intracellular GSH to produce PSSG [15]. S-glutathionylated proteins are mainly catalyzed in reverse by glutathionyl-mixed-disulfide oxidoreductases, such as glutaredoxins (Glrx) [16]. ...
... Glrx1 has a molecular weight of 12 kDa and belongs to the Glrx family. It is considered to be a major deglutathionylation enzyme that has a significant influence on redox pathway and homeostasis [15,16]. Glrx1 is highly expressed in the liver and related to liver fibrosis [17], non-alcoholic fatty liver [18,19], and alcoholic induced liver injury [20,21], but it remains uncertain whether Glrx1 participates in APAP-caused liver damage. ...
Excessive N-acetyl-p-benzoquinone imine (NAPQI) formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen (APAP) overdose caused acute liver failure (ALF). S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity. Glutaredoxin-1 (Glrx1), a glutathione-specific thioltransferase, is a primary enzyme to catalyze deglutathionylation. The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP. The Glrx1 knockout mice (Glrx1−/−) and liver-specific overexpression of Glrx1 (AAV8-Glrx1) mice were produced and underwent APAP-induced ALF. Pirfenidone (PFD), a potential inducer of Glrx1, was administrated preceding APAP to assess its protective effects. Our results revealed that the hepatic total protein S-glutathionylation (PSSG) increased and the Glrx1 level reduced in mice after APAP toxicity. Glrx1−/− mice were more sensitive to APAP overdose, with higher oxidative stress and more toxic metabolites of APAP. This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p450 3a11 (Cyp3a11), which likely increased the activity of Cyp3a11. Conversely, AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11, which reduced the toxic metabolites of APAP and oxidative stress. PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress. We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose. Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.
... The conjugation and removal of GSH from protein thiols is a highly regulated and critical biological process. S-glutathionylation affects all major classes of proteins, controls the activity of both thioredoxin and peroxiredoxin redox systems (reviewed in ref. 9) and provides protection from irreversible overoxidation by allowing restitution of the original thiol group via the glutaredoxin system 43 . GLRX regulates the balance of glutathionylated proteins by performing deglutathionylation with greater efficiency than any other cytosolic oxidoreductase, including thioredoxins, in physiological settings 44 . ...
Protein-S-glutathionylation is a post-translational modification involving the conjugation of glutathione to protein thiols, which can modulate the activity and structure of key cellular proteins. Glutaredoxins (GLRX) are oxidoreductases that regulate this process by performing deglutathionylation. However, GLRX has five cysteines that are potentially vulnerable to oxidative modification, which is associated with GLRX aggregation and loss of activity. To date, GLRX cysteines that are oxidatively modified and their relative susceptibilities remain unknown. We utilized molecular modeling approaches, activity assays using recombinant GLRX, coupled with site-directed mutagenesis of each cysteine both individually and in combination to address the oxidizibility of GLRX cysteines. These approaches reveal that C8 and C83 are targets for S-glutathionylation and oxidation by hydrogen peroxide in vitro. In silico modeling and experimental validation confirm a prominent role of C8 for dimer formation and aggregation. Lastly, combinatorial mutation of C8, C26, and C83 results in increased activity of GLRX and resistance to oxidative inactivation and aggregation. Results from these integrated computational and experimental studies provide insights into the relative oxidizability of GLRX’s cysteines and have implications for the use of GLRX as a therapeutic in settings of dysregulated protein glutathionylation.
