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Thiol-Based Redox Regulation of Cellular and Organismal Function

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "ROS, RNS and RSS".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 37973

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Special Issue Editor

Prof. Dr. Bruce Morgan

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Guest Editor

Institute of Biochemistry, Universität des Saarlandes, 66123 Saarbrücken, Germany
Interests: genetically encoded redox sensors; redox regulation of metabolism; glutathione homeostasis; H₂O₂ homeostasis

Special Issue Information

Dear Colleagues,

Thiol groups in protein cysteine residues are susceptible to a wide range of post-translational oxidative modifications, including but not limited to disulfide bond formation, S-glutathionylation, S-nitrosylation, persulfidation, and sulfenylation. Such cysteine redox modifications can occur in numerous proteins, including metabolic enzymes, transcription factors, and kinases, and can serve to modulate or regulate protein function.

However, our understanding of protein thiol redox modifications remains remarkably limited in many aspects. For example, we do not even have a clear understanding of how many proteins are susceptible to thiol redox-based regulation of their activity or function. Furthermore, the mechanism of protein thiol oxidation remains to be elucidated in most cases. Some thiol redox modifications are relatively short-lived and unstable. It is possible that such redox modifications may simply represent an intermediate step towards a more stable modification, for example, a disulfide bond; however, this remains under debate. In any case, it is increasingly accepted that the oxidative modification of cysteine thiol groups is likely to be tightly controlled. For example, thiol peroxidase-based redox relays are one important mechanism for ensuring specificity and sensitivity of H₂O₂-mediated protein thiol oxidation. Elucidating the mechanism of all types of thiol oxidation remains an exciting challenge. However, there is light at the end of the tunnel as a plethora of new tools, techniques, and approaches are enabling us to rapidly shed new light on these intriguing questions.

In this Special Issue, we invite researchers to contribute both original research articles as well as review articles. We particularly welcome articles that offer strong new mechanistic insights on all aspects of oxidative protein thiol modifications, from the mechanism and regulation of thiol oxidation through to the impact on cellular or organismal function, as well as articles that focus on novel technical or methodological approaches.

Prof. Dr. Bruce Morgan
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Thiol-based redox regulation
Thiol-based redox signaling
Thiol oxidation
S-nitrosylation
Persulfidation
Disulfide bond
S-glutathionylation

Published Papers (11 papers)

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Research

Jump to: Review

21 pages, 4879 KiB

Open AccessArticle

Effects of Serine or Threonine in the Active Site of Typical 2-Cys Prx on Hyperoxidation Susceptibility and on Chaperone Activity

by Carlos A. Tairum, Melina Cardoso Santos, Carlos Alexandre Breyer, Ana Laura Pires de Oliveira, Vitoria Isabela Montanhero Cabrera, Guilherme Toledo-Silva, Gustavo Maruyama Mori, Marcos Hikari Toyama, Luis Eduardo Soares Netto and Marcos Antonio de Oliveira

Antioxidants 2021, 10(7), 1032; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071032 - 25 Jun 2021

Cited by 6 | Viewed by 2399

Abstract

Typical 2-Cys peroxiredoxins (2-Cys Prx) are ubiquitous Cys-based peroxidases, which are stable as decamers in the reduced state, and may dissociate into dimers upon disulfide bond formation. A peroxidatic Cys (C_P) takes part of a catalytic triad, together with a Thr/Ser and an Arg. Previously, we described that the presence of Ser (instead of Thr) in the active site stabilizes yeast 2-Cys Prx as decamers. Here, we compared the hyperoxidation susceptibilities of yeast 2-Cys Prx. Notably, 2-Cys Prx containing Ser (named here Ser-Prx) were more resistant to hyperoxidation than enzymes containing Thr (Thr-Prx). In silico analysis revealed that Thr-Prx are more frequent in all domains of life, while Ser-Prx are more abundant in bacteria. As yeast 2-Cys Prx, bacterial Ser-Prx are more stable as decamers than Thr-Prx. However, bacterial Ser-Prx were only slightly more resistant to hyperoxidation than Thr-Prx. Furthermore, in all cases, organic hydroperoxide inhibited more the peroxidase activities of 2-Cys Prx than hydrogen peroxide. Moreover, bacterial Ser-Prx displayed increased thermal resistance and chaperone activity, which may be related with its enhanced stability as decamers compared to Thr-Prx. Therefore, the single substitution of Thr by Ser in the catalytic triad results in profound biochemical and structural differences in 2-Cys Prx. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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15 pages, 2316 KiB

Open AccessArticle

Atypical Iron-Sulfur Cluster Binding, Redox Activity and Structural Properties of Chlamydomonas reinhardtii Glutaredoxin 2

by Thomas Roret, Bo Zhang, Anna Moseler, Tiphaine Dhalleine, Xing-Huang Gao, Jérémy Couturier, Stéphane D. Lemaire, Claude Didierjean, Michael K. Johnson and Nicolas Rouhier

Antioxidants 2021, 10(5), 803; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050803 - 19 May 2021

Cited by 3 | Viewed by 2453

Abstract

Glutaredoxins (GRXs) are thioredoxin superfamily members exhibiting thiol-disulfide oxidoreductase activity and/or iron-sulfur (Fe-S) cluster binding capacities. These properties are determined by specific structural factors. In this study, we examined the capacity of the class I Chlamydomonas reinhardtii GRX2 recombinant protein to catalyze both protein glutathionylation and deglutathionylation reactions using a redox sensitive fluorescent protein as a model protein substrate. We observed that the catalytic cysteine of the CPYC active site motif of GRX2 was sufficient for catalyzing both reactions in the presence of glutathione. Unexpectedly, spectroscopic characterization of the protein purified under anaerobiosis showed the presence of a [2Fe-2S] cluster despite having a presumably inadequate active site signature, based on past mutational analyses. The spectroscopic characterization of cysteine mutated variants together with modeling of the Fe–S cluster-bound GRX homodimer from the structure of an apo-GRX2 indicate the existence of an atypical Fe–S cluster environment and ligation mode. Overall, the results further delineate the biochemical and structural properties of conventional GRXs, pointing to the existence of multiple factors more complex than anticipated, sustaining the capacity of these proteins to bind Fe–S clusters. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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12 pages, 2732 KiB

Open AccessArticle

The Mitochondria-to-Cytosol H₂O₂ Gradient Is Caused by Peroxiredoxin-Dependent Cytosolic Scavenging

by Laura de Cubas, Valeriy V. Pak, Vsevolod V. Belousov, José Ayté and Elena Hidalgo

Antioxidants 2021, 10(5), 731; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050731 - 06 May 2021

Cited by 20 | Viewed by 3572

Abstract

Fluorescent protein-based reporters used to measure intracellular H₂O₂ were developed to overcome the limitations of small permeable dyes. The two major families of genetically encoded redox reporters are the reduction-oxidation sensitive green fluorescent protein (roGFP)-based proteins fused to peroxiredoxins and HyPer and derivatives. We have used the most sensitive probes of each family, roGFP2-Tpx1.C169S and HyPer7, to monitor steady-state and fluctuating levels of peroxides in fission yeast. While both are able to monitor the nanomolar fluctuations of intracellular H₂O₂, the former is two-five times more sensitive than HyPer7, and roGFP2-Tpx1.C169S is partially oxidized in the cytosol of wild-type cells while HyPer7 is fully reduced. We have successfully expressed HyPer7 in the mitochondrial matrix, and it is ~40% oxidized, suggesting higher steady-state levels of peroxides, in the low micromolar range, than in the cytosol. Cytosolic HyPer7 can detect negligible H₂O₂ in the cytosol from mitochondrial origin unless the main H₂O₂ scavenger, the cytosolic peroxiredoxin Tpx1, is absent, while mitochondrial HyPer7 is oxidized to the same extent in wild-type and ∆tpx1 cells. We conclude that there is a bidirectional flux of H₂O₂ across the matrix and the cytosol, but Tpx1 rapidly and efficiently scavenges mitochondrial-generated peroxides and stops their steady-state cytosolic levels rising. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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20 pages, 3913 KiB

Open AccessArticle

The Human 2-Cys Peroxiredoxins form Widespread, Cysteine-Dependent- and Isoform-Specific Protein-Protein Interactions

by Loes van Dam, Marc Pagès-Gallego, Paulien E. Polderman, Robert M. van Es, Boudewijn M. T. Burgering, Harmjan R. Vos and Tobias B. Dansen

Antioxidants 2021, 10(4), 627; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10040627 - 20 Apr 2021

Cited by 19 | Viewed by 5274

Abstract

Redox signaling is controlled by the reversible oxidation of cysteine thiols, a post-translational modification triggered by H₂O₂ acting as a second messenger. However, H₂O₂ actually reacts poorly with most cysteine thiols and it is not clear how H₂O₂ discriminates between cysteines to trigger appropriate signaling cascades in the presence of dedicated H₂O₂ scavengers like peroxiredoxins (PRDXs). It was recently suggested that peroxiredoxins act as peroxidases and facilitate H₂O₂-dependent oxidation of redox-regulated proteins via disulfide exchange reactions. It is unknown how the peroxiredoxin-based relay model achieves the selective substrate targeting required for adequate cellular signaling. Using a systematic mass-spectrometry-based approach to identify cysteine-dependent interactors of the five human 2-Cys peroxiredoxins, we show that all five human 2-Cys peroxiredoxins can form disulfide-dependent heterodimers with a large set of proteins. Each isoform displays a preference for a subset of disulfide-dependent binding partners, and we explore isoform-specific properties that might underlie this preference. We provide evidence that peroxiredoxin-based redox relays can proceed via two distinct molecular mechanisms. Altogether, our results support the theory that peroxiredoxins could play a role in providing not only reactivity but also selectivity in the transduction of peroxide signals to generate complex cellular signaling responses. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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23 pages, 2576 KiB

Open AccessArticle

The Phosphofructokinase Isoform AtPFK5 Is a Novel Target of Plastidic Thioredoxin-f-Dependent Redox Regulation

by Natalia Hess, Simon Richter, Michael Liebthal, Karl-Josef Dietz and Angelika Mustroph

Antioxidants 2021, 10(3), 401; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030401 - 07 Mar 2021

Cited by 2 | Viewed by 2842

Abstract

The chloroplast primary metabolism is of central importance for plant growth and performance. Therefore, it is tightly regulated in order to adequately respond to multiple environmental conditions. A major fluctuation that plants experience each day is the change between day and night, i.e., the change between assimilation and dissimilation. Among other mechanisms, thioredoxin-mediated redox regulation is an important component of the regulation of plastid-localized metabolic enzymes. While assimilatory processes such as the Calvin–Benson cycle are activated under illumination, i.e., under reducing conditions, carbohydrate degradation is switched off during the day. Previous analyses have identified enzymes of the oxidative pentose phosphate pathway to be inactivated by reduction through thioredoxins. In this work, we present evidence that an enzyme of the plastidic glycolysis, the phosphofructokinase isoform AtPFK5, is also inactivated through reduction by thioredoxins, namely by thioredoxin-f. With the help of chemical oxidation, mutant analyses and further experiments, the highly conserved motif CXDXXC in AtPFK5 was identified as the target sequence for this regulatory mechanism. However, knocking out this isoform in plants had only very mild effects on plant growth and performance, indicating that the complex primary metabolism in plants can overcome a lack in AtPFK5 activity. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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20 pages, 19111 KiB

Open AccessArticle

Evaluation of Cysteine Metabolism in the Rat Liver and Kidney Following Intravenous Cocaine Administration and Abstinence

by Danuta Kowalczyk-Pachel, Małgorzata Iciek, Anna Bilska-Wilkosz, Magdalena Górny, Joanna Jastrzębska, Kinga Kamińska, Paulina Dudzik, Małgorzata Filip and Elżbieta Lorenc-Koci

Antioxidants 2021, 10(1), 74; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10010074 - 08 Jan 2021

Cited by 1 | Viewed by 2336

Abstract

Many toxic effects of cocaine are attributed to reactive oxygen species (ROS) generated during its metabolism. Recently, it has been suggested that the biological action of ROS is often confused with endogenously generated reactive sulfur species (RSS). The aim of this study was to evaluate the impact of cocaine on thiols and RSS in the rat liver and kidney in the drug self-administration (SA) paradigm and the cocaine yoked delivery model (YC) followed by drug abstinence with extinction training. The level of thiols as well as RSS formed during anaerobic metabolism of cysteine and sulfate were assayed. In addition, the activity of enzymes involved in RSS formation and glutathione metabolism were determined. In the liver, following direct cocaine administration (SA and YC), the RSS levels decreased, while in the kidneys, cocaine increased the RSS contents in both groups. These changes were maintained in these tissues during drug abstinence. The level of sulfates was changed by cocaine only in the liver. In the kidney, cocaine shifted cysteine metabolism towards an anaerobic pathway. Our study demonstrates for the first time the changes in cysteine metabolism and thiol levels in the liver and kidney of rats after cocaine self-administration and abstinence. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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14 pages, 4064 KiB

Open AccessArticle

The Sulfilimine Analogue of Allicin, S-Allyl-S-(S-allyl)-N-Cyanosulfilimine, Is Antimicrobial and Reacts with Glutathione

by Tobias Horn, Wolfgang Bettray, Ulrike Noll, Felix Krauskopf, Meng-Ruo Huang, Carsten Bolm, Alan J. Slusarenko and Martin C. H. Gruhlke

Antioxidants 2020, 9(11), 1086; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9111086 - 04 Nov 2020

Cited by 9 | Viewed by 2695

Abstract

When cells of garlic (Allium sativum) are disrupted by wounding, they produce the defense substance allicin (diallylthiosulfinate). Allicin is an efficient thiol trap and readily passes through cell membranes into the cytosol, where it behaves as a redox toxin by oxidizing the cellular glutathione (GSH) pool and producing S-allylmercaptoglutathione (GSSA). An N-cyanosulfilimine analogue of allicin (CSA), which was predicted to have similar reactivity towards thiol groups but be more stable in storage, was synthesized and its properties investigated. Similarly to allicin, CSA was shown to inhibit the growth of various bacteria, a fungus (baker’s yeast), and Arabidopsis roots. A chemogenetic screen showed that yeast mutants with compromised GSH levels and metabolism were hypersensitive to CSA. GSH reacted with CSA to produce allyltrisulfanylglutathione (GS₃A), which was a white solid virtually insoluble in water. Yeast Δgsh1 mutants are unable to synthesize GSH because they lack the γ-glutamylcysteine synthetase (GSH1) gene, and they are unable to grow without GSH supplementation in the medium. GS₃A in the growth medium supported the auxotrophic requirement for GSH in Δgsh1 mutants. This result suggests that GS₃A is being reduced to GSH in vivo, possibly by the enzyme glutathione reductase (GR), which has been shown to accept GSSA as a substrate. The results suggest that CSA has a mode of action similar to allicin and is effective at similar concentrations. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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Review

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14 pages, 1100 KiB

Open AccessReview

Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease

by Bindu D. Paul

Antioxidants 2021, 10(9), 1468; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091468 - 15 Sep 2021

Cited by 10 | Viewed by 2971

Abstract

Huntington’s disease (HD) is caused by expansion of polyglutamine repeats in the protein huntingtin, which affects the corpus striatum of the brain. The polyglutamine repeats in mutant huntingtin cause its aggregation and elicit toxicity by affecting several cellular processes, which include dysregulated organellar stress responses. The Golgi apparatus not only plays key roles in the transport, processing, and targeting of proteins, but also functions as a sensor of stress, signaling through the Golgi stress response. Unlike the endoplasmic reticulum (ER) stress response, the Golgi stress response is relatively unexplored. This review focuses on the molecular mechanisms underlying the Golgi stress response and its intersection with cysteine metabolism in HD. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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27 pages, 7318 KiB

Open AccessReview

The Multifaceted Bacterial Cysteine Desulfurases: From Metabolism to Pathogenesis

by Mayashree Das, Arshiya Dewan, Somnath Shee and Amit Singh

Antioxidants 2021, 10(7), 997; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10070997 - 23 Jun 2021

Cited by 12 | Viewed by 4334

Abstract

Living cells have developed a relay system to efficiently transfer sulfur (S) from cysteine to various thio-cofactors (iron-sulfur (Fe-S) clusters, thiamine, molybdopterin, lipoic acid, and biotin) and thiolated tRNA. The presence of such a transit route involves multiple protein components that allow the flux of S to be precisely regulated as a function of environmental cues to avoid the unnecessary accumulation of toxic concentrations of soluble sulfide (S²⁻). The first enzyme in this relay system is cysteine desulfurase (CSD). CSD catalyzes the release of sulfane S from L-cysteine by converting it to L-alanine by forming an enzyme-linked persulfide intermediate on its conserved cysteine residue. The persulfide S is then transferred to diverse acceptor proteins for its incorporation into the thio-cofactors. The thio-cofactor binding-proteins participate in essential and diverse cellular processes, including DNA repair, respiration, intermediary metabolism, gene regulation, and redox sensing. Additionally, CSD modulates pathogenesis, antibiotic susceptibility, metabolism, and survival of several pathogenic microbes within their hosts. In this review, we aim to comprehensively illustrate the impact of CSD on bacterial core metabolic processes and its requirement to combat redox stresses and antibiotics. Targeting CSD in human pathogens can be a potential therapy for better treatment outcomes. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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18 pages, 1752 KiB

Open AccessReview

Impact of Hydrogen Peroxide on Protein Synthesis in Yeast

by Cecilia Picazo and Mikael Molin

Antioxidants 2021, 10(6), 952; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10060952 - 12 Jun 2021

Cited by 14 | Viewed by 4141

Abstract

Cells must be able to respond and adapt to different stress conditions to maintain normal function. A common response to stress is the global inhibition of protein synthesis. Protein synthesis is an expensive process consuming much of the cell’s energy. Consequently, it must be tightly regulated to conserve resources. One of these stress conditions is oxidative stress, resulting from the accumulation of reactive oxygen species (ROS) mainly produced by the mitochondria but also by other intracellular sources. Cells utilize a variety of antioxidant systems to protect against ROS, directing signaling and adaptation responses at lower levels and/or detoxification as levels increase to preclude the accumulation of damage. In this review, we focus on the role of hydrogen peroxide, H₂O₂, as a signaling molecule regulating protein synthesis at different levels, including transcription and various parts of the translation process, e.g., initiation, elongation, termination and ribosome recycling. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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12 pages, 2511 KiB

Open AccessReview

Selenomethionine: A Pink Trojan Redox Horse with Implications in Aging and Various Age-Related Diseases

by Muhammad Jawad Nasim, Mhd Mouayad Zuraik, Ahmad Yaman Abdin, Yannick Ney and Claus Jacob

Antioxidants 2021, 10(6), 882; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10060882 - 31 May 2021

Cited by 23 | Viewed by 3879

Abstract

Selenium is an essential trace element. Although this chalcogen forms a wide variety of compounds, there are surprisingly few small-molecule organic selenium compounds (OSeCs) in biology. Besides its more prominent relative selenocysteine (SeCys), the amino acid selenomethionine (SeMet) is one example. SeMet is synthesized in plants and some fungi and, via nutrition, finds its way into mammalian cells. In contrast to its sulfur analog methionine (Met), SeMet is extraordinarily redox active under physiological conditions and via its catalytic selenide (RSeR’)/selenoxide (RSe(O)R’) couple provides protection against reactive oxygen species (ROS) and other possibly harmful oxidants. In contrast to SeCys, which is incorporated via an eloquent ribosomal mechanism, SeMet can enter such biomolecules by simply replacing proteinogenic Met. Interestingly, eukaryotes, such as yeast and mammals, also metabolize SeMet to a small family of reactive selenium species (RSeS). Together, SeMet, proteins containing SeMet and metabolites of SeMet form a powerful triad of redox-active metabolites with a plethora of biological implications. In any case, SeMet and its family of natural RSeS provide plenty of opportunities for studies in the fields of nutrition, aging, health and redox biology. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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