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Interactions of Redox-Active Proteins and Their Substrates

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

Deadline for manuscript submissions: closed (10 February 2024) | Viewed by 21371

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Special Issue Editor

Dr. Alexios Vlamis-Gardikas

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Guest Editor

Department of Chemistry, University of Patras, 26504 Rion, Greece
Interests: thioredoxins; glutaredoxins; thioredoxin reductase; toxins/antitoxins; antimicrobials

Special Issue Information

Dear Colleagues,

The identification and characterization of protein interactions is required to understand protein function and the organization and regulation of cellular life. From a biochemical point of view, life can be regarded as a carefully regulated flow of electrons from donor compounds to acceptors of higher reduction potential. In most cells the flow starts from the universal electron donor glucose to acceptors, in processes that ultimately generate energy in the form of ATP. Distinct protein networks mediate this regulated flow acting as electron transporters while other proteins may have their activities affected by deviations of the electron flow. Apart from glucose, complementary reducing equivalents may be provided by NADPH (sometimes produced by glucose itself via the pentose phosphate pathway) to be used in other redox-involving processes such as the reduction of ribonucleotides to deoxyribonucleotides, the assimilation of sulphur, or cell signalling or may be used by networks of “antioxidant” proteins that may reverse undesired oxidations. This special issue is essentially an update on the interactions of proteins participating in cellular electron flows or being affected by them. Structural elements of the interactions, the interacting species and the kinetic properties of interactions are well within the scope of the special issue.

Dr. Alexios Vlamis-Gardikas
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

interaction
electron flow
redox-active proteins
thioredoxin
glutaredoxin

Published Papers (7 papers)

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Research

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35 pages, 7577 KiB

Open AccessArticle

Distinct or Overlapping Areas of Mitochondrial Thioredoxin 2 May Be Used for Its Covalent and Strong Non-Covalent Interactions with Protein Ligands

by Charalampos Ntallis, Haralampos Tzoupis, Theodore Tselios, Christos T. Chasapis and Alexios Vlamis-Gardikas

Antioxidants 2024, 13(1), 15; https://doi.org/10.3390/antiox13010015 - 20 Dec 2023

Viewed by 1092

Abstract

In silico approaches were employed to examine the characteristics of interactions between human mitochondrial thioredoxin 2 (HsTrx2) and its 38 previously identified mitochondrial protein ligands. All interactions appeared driven mainly by electrostatic forces. The statistically significant residues of HsTrx2 for interactions were characterized as “contact hot spots”. Since these were identical/adjacent to putative thermodynamic hot spots, an energy network approach identified their neighbors to highlight possible contact interfaces. Three distinct areas for binding emerged: (i) one around the active site for covalent interactions, (ii) another antipodal to the active site for strong non-covalent interactions, and (iii) a third area involved in both kinds of interactions. The contact interfaces of HsTrx2 were projected as respective interfaces for Escherichia coli Trx1 (EcoTrx1), 2, and HsTrx1. Comparison of the interfaces and contact hot spots of HsTrx2 to the contact residues of EcoTx1 and HsTrx1 from existing crystal complexes with protein ligands supported the hypothesis, except for a part of the cleft/groove adjacent to Trp³⁰ preceding the active site. The outcomes of this study raise the possibility for the rational design of selective inhibitors for the interactions of HsTrx2 with specific protein ligands without affecting the entirety of the functions of the Trx system. Full article

(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)

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14 pages, 2422 KiB

Open AccessArticle

Oxidation of Arabidopsis thaliana COX19 Using the Combined Action of ERV1 and Glutathione

by Flavien Zannini, Johannes M. Herrmann, Jérémy Couturier and Nicolas Rouhier

Antioxidants 2023, 12(11), 1949; https://doi.org/10.3390/antiox12111949 - 01 Nov 2023

Viewed by 963

Abstract

Protein import and oxidative folding within the intermembrane space (IMS) of mitochondria relies on the MIA40–ERV1 couple. The MIA40 oxidoreductase usually performs substrate recognition and oxidation and is then regenerated by the FAD-dependent oxidase ERV1. In most eukaryotes, both proteins are essential; however, MIA40 is dispensable in Arabidopsis thaliana. Previous complementation experiments have studied yeast mia40 mutants expressing a redox inactive, but import-competent versions of yeast Mia40 using A. thaliana ERV1 (AtERV1) suggest that AtERV1 catalyzes the oxidation of MIA40 substrates. We assessed the ability of both yeast and Arabidopsis MIA40 and ERV1 recombinant proteins to oxidize the apo-cytochrome reductase CCMH and the cytochrome c oxidase assembly protein COX19, a typical MIA40 substrate, in the presence or absence of glutathione, using in vitro cysteine alkylation and cytochrome c reduction assays. The presence of glutathione used at a physiological concentration and redox potential was sufficient to support the oxidation of COX19 by AtERV1, providing a likely explanation for why MIA40 is not essential for the import and oxidative folding of IMS-located proteins in Arabidopsis. The results point to fundamental biochemical differences between Arabidopsis and yeast ERV1 in catalyzing protein oxidation. Full article

(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)

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21 pages, 10266 KiB

Open AccessArticle

Functional Diversity of Homologous Oxidoreductases—Tuning of Substrate Specificity by a FAD-Stacking Residue for Iron Acquisition and Flavodoxin Reduction

by Marta Hammerstad, Anne Kristine Rugtveit, Sondov Dahlen, Hilde Kristin Andersen and Hans-Petter Hersleth

Antioxidants 2023, 12(6), 1224; https://doi.org/10.3390/antiox12061224 - 06 Jun 2023

Viewed by 1460

Abstract

Although bacterial thioredoxin reductase-like ferredoxin/flavodoxin NAD(P)⁺ oxidoreductases (FNRs) are similar in terms of primary sequences and structures, they participate in diverse biological processes by catalyzing a range of different redox reactions. Many of the reactions are critical for the growth, survival of, and infection by pathogens, and insight into the structural basis for substrate preference, specificity, and reaction kinetics is crucial for the detailed understanding of these redox pathways. Bacillus cereus (Bc) encodes three FNR paralogs, two of which have assigned distinct biological functions in bacillithiol disulfide reduction and flavodoxin (Fld) reduction. Bc FNR2, the endogenous reductase of the Fld-like protein NrdI, belongs to a distinct phylogenetic cluster of homologous oxidoreductases containing a conserved His residue stacking the FAD cofactor. In this study, we have assigned a function to FNR1, in which the His residue is replaced by a conserved Val, in the reduction of the heme-degrading monooxygenase IsdG, ultimately facilitating the release of iron in an important iron acquisition pathway. The Bc IsdG structure was solved, and IsdG-FNR1 interactions were proposed through protein–protein docking. Mutational studies and bioinformatics analyses confirmed the importance of the conserved FAD-stacking residues on the respective reaction rates, proposing a division of FNRs into four functionally unique sequence similarity clusters likely related to the nature of this residue. Full article

(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)

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17 pages, 11756 KiB

Open AccessArticle

Disruption of Bacterial Thiol-Dependent Redox Homeostasis by Magnolol and Honokiol as an Antibacterial Strategy

by Yanfang Ouyang, Xuewen Tang, Ying Zhao, Xin Zuo, Xiaoyuan Ren, Jun Wang, Lili Zou and Jun Lu

Antioxidants 2023, 12(6), 1180; https://doi.org/10.3390/antiox12061180 - 30 May 2023

Cited by 1 | Viewed by 1573

Abstract

Some traditional Chinese medicines (TCMs) possess various redox-regulation properties, but whether the redox regulation contributes to antibacterial mechanisms is not known. Here, ginger juice processed Magnoliae officinalis cortex (GMOC) was found to show strong antibacterial activities against some Gram-positive bacteria, but not Gram-negative bacteria including E. coli, while the redox-related transcription factor oxyR deficient E. coli mutant was sensitive to GMOC. In addition, GMOC and its main ingredients, magnolol and honokiol, exhibited inhibitory effects on the bacterial thioredoxin (Trx) system, a major thiol-dependent disulfide reductase system in bacteria. The effects of magnolol and honokiol on cellular redox homeostasis were further verified by elevation of the intracellular ROS levels. The therapeutic efficacies of GMOC, magnolol and honokiol were further verified in S. aureus-caused mild and acute peritonitis mouse models. Treatments with GMOC, magnolol and honokiol significantly reduced the bacterial load, and effectively protected the mice from S. aureus-caused peritonitis infections. Meanwhile, magnolol and honokiol produced synergistic effects when used in combination with several classic antibiotics. These results strongly suggest that some TCMs may exert their therapeutic effects via targeting the bacterial thiol-dependent redox system. Full article

(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)

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19 pages, 3503 KiB

Open AccessArticle

The Functional Relationship between NADPH Thioredoxin Reductase C, 2-Cys Peroxiredoxins, and m-Type Thioredoxins in the Regulation of Calvin–Benson Cycle and Malate-Valve Enzymes in Arabidopsis

by Víctor Delgado-Requerey, Francisco Javier Cejudo and María-Cruz González

Antioxidants 2023, 12(5), 1041; https://doi.org/10.3390/antiox12051041 - 03 May 2023

Cited by 2 | Viewed by 1565

Abstract

The concerted regulation of chloroplast biosynthetic pathways and NADPH extrusion via malate valve depends on f and m thioredoxins (Trxs). The finding that decreased levels of the thiol-peroxidase 2-Cys peroxiredoxin (Prx) suppress the severe phenotype of Arabidopsis mutants lacking NADPH-dependent Trx reductase C (NTRC) and Trxs f uncovered the central function of the NTRC-2-Cys-Prx redox system in chloroplast performance. These results suggest that Trxs m are also regulated by this system; however, the functional relationship between NTRC, 2-Cys Prxs, and m-type Trxs is unknown. To address this issue, we generated Arabidopsis thaliana mutants combining deficiencies in NTRC, 2-Cys Prx B, Trxs m1, and m4. The single trxm1 and trxm4 mutants showed a wild-type phenotype, growth retardation being noticed only in the trxm1m4 double mutant. Moreover, the ntrc-trxm1m4 mutant displayed a more severe phenotype than the ntrc mutant, as shown by the impaired photosynthetic performance, altered chloroplast structure, and defective light-dependent reduction in the Calvin–Benson cycle and malate-valve enzymes. These effects were suppressed by the decreased contents of 2-Cys Prx, since the quadruple ntrc-trxm1m4-2cpb mutant displayed a wild-type-like phenotype. These results show that the activity of m-type Trxs in the light-dependent regulation of biosynthetic enzymes and malate valve is controlled by the NTRC-2-Cys-Prx system. Full article

(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)

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Review

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17 pages, 2191 KiB

Open AccessReview

Deciphering the Role of Selenoprotein M

by Lance G. A. Nunes, Antavius Cain, Cody Comyns, Peter R. Hoffmann and Natalie Krahn

Antioxidants 2023, 12(11), 1906; https://doi.org/10.3390/antiox12111906 - 25 Oct 2023

Viewed by 1241

Abstract

Selenocysteine (Sec), the 21st amino acid, is structurally similar to cysteine but with a sulfur to selenium replacement. This single change retains many of the chemical properties of cysteine but often with enhanced catalytic and redox activity. Incorporation of Sec into proteins is unique, requiring additional translation factors and multiple steps to insert Sec at stop (UGA) codons. These Sec-containing proteins (selenoproteins) are found in all three domains of life where they often are involved in cellular homeostasis (e.g., reducing reactive oxygen species). The essential role of selenoproteins in humans requires us to maintain appropriate levels of selenium, the precursor for Sec, in our diet. Too much selenium is also problematic due to its toxic effects. Deciphering the role of Sec in selenoproteins is challenging for many reasons, one of which is due to their complicated biosynthesis pathway. However, clever strategies are surfacing to overcome this and facilitate production of selenoproteins. Here, we focus on one of the 25 human selenoproteins, selenoprotein M (SELENOM), which has wide-spread expression throughout our tissues. Its thioredoxin motif suggests oxidoreductase function; however, its mechanism and functional role(s) are still being uncovered. Furthermore, the connection of both high and low expression levels of SELENOM to separate diseases emphasizes the medical application for studying the role of Sec in this protein. In this review, we aim to decipher the role of SELENOM through detailing and connecting current evidence. With multiple proposed functions in diverse tissues, continued research is still necessary to fully unveil the role of SELENOM. Full article

(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)

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16 pages, 1351 KiB

Open AccessReview

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

by Jaewang Lee and Jong-Lyel Roh

Antioxidants 2022, 11(12), 2444; https://doi.org/10.3390/antiox11122444 - 11 Dec 2022

Cited by 18 | Viewed by 12433

Abstract

SLC7A11 is a cell transmembrane protein composing the light chain of system xc⁻, transporting extracellular cystine into cells for cysteine production and GSH biosynthesis. SLC7A11 is a critical gateway for redox homeostasis by maintaining the cellular levels of GSH that counter cellular oxidative stress and suppress ferroptosis. SLC7A11 is overexpressed in various human cancers and regulates tumor development, proliferation, metastasis, microenvironment, and treatment resistance. Upregulation of SLC7A11 in cancers is needed to adapt to high oxidative stress microenvironments and maintain cellular redox homeostasis. High basal ROS levels and SLC7A11 dependences in cancer cells render them vulnerable to further oxidative stress. Therefore, cyst(e)ine depletion may be an effective new strategy for cancer treatment. However, the effectiveness of the SLC7A11 inhibitors or cyst(e)inase has been established in many preclinical studies but has not reached the stage of clinical trials for cancer patients. A better understanding of cysteine and SLC7A11 functions regulating and interacting with redox-active proteins and their substrates could be a promising strategy for cancer treatment. Therefore, this review intends to understand the role of cysteine in antioxidant and redox signaling, the regulators of cysteine bioavailability in cancer, the role of SLC7A11 linking cysteine redox signaling in cancer metabolism and targeting SLC7A11 for novel cancer therapeutics. Full article

(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)

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