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Structure, function, and mechanism of thioredoxin proteins Vrije Universiteit Brussel

Jean François Collet, Joris Messens
Thioredoxins are ubiquitous antioxidant enzymes that play important roles in many health-related cellular processes. As such, the fundamental knowledge of how these enzymes work is of prime importance for understanding cellular redox mechanisms and for laying the ground for the development of future therapeutic approaches. Over the past 40 years, a really impressive amount of data has been published on thioredoxins. Here, we review the most ...

How thioredoxin dissociates its mixed disulfide Vrije Universiteit Brussel

Goedele Roos, Nicolas Foloppe, Koen Van Laer, Lode Wyns, Lennart Nilsson, Paul Geerlings, Joris Messens
The dissociation mechanism of the thioredoxin (Trx) mixed disulfide complexes is unknown and has been debated for more than twenty years. Specifically, opposing arguments for the activation of the nucleophilic cysteine as a thiolate during the dissociation of the complex have been put forward. As a key model, the complex between Trx and its endogenous substrate, arsenate reductase (ArsC), was used. In this structure, a Cys29(Trx)-Cys89(ArsC) ...

Coupling of domain swapping to kinetic stability in a thioredoxin mutant. Vrije Universiteit Brussel

Abel Garcia Pino, Sergio Martinez Rodriguez, Khadija Wahni, Lode Wyns, Remy Loris, Joris Messens
The thioredoxin (Trx) fold is a small monomeric domain that is ubiquitous in redox-active enzymes. Trxs are characterized by a typical WCGPC active-site sequence motif. A single active-site mutation of the tryptophan to an alanine in Staphylococcus aureus Trx converts the oxidized protein into a biologically inactive domain-swapped dimer. While the monomeric protein unfolds reversibly in a two-state manner, the oxidized dimeric form is ...

NrdH-redoxin of Mycobacterium tuberculosis and Corynebacterium glutamicum dimerizes at high protein concentration and exclusively receives electrons from thioredoxin reductase Vrije Universiteit Brussel

Koen Van Laer, Aleksandra Dziewulska, Marcus Fislage, Khadija Wahni, Abderahim Hbeddou, Jean-Francois Collet, Wim Versées, Luis M Mateos, Veronica Tamu Dufe, Joris Messens, et al.

NrdH-redoxins are small reductases with a high amino acid sequence similarity with glutaredoxins and mycoredoxins but with a thioredoxin-like activity. They function as the electron donor for class Ib ribonucleotide reductases, which convert ribonucleotides into deoxyribonucleotides. We solved the x-ray structure of oxidized NrdH-redoxin from Corynebacterium glutamicum (Cg) at 1.5 Å resolution. Based on this monomeric structure, we built a ...

The conserved active site tryptophan of thioredoxin has no effect on its redox properties Vrije Universiteit Brussel

Goedele Roos, Paul Geerlings, Joris Messens

In Staphylococcus aureus thioredoxin (Trx) it has been shown that mutation of the conserved active site tryptophan residue (Trp28) has a large effect on the protein stability, on the pKa of the nucleophilic cysteine and on the redox potential. Since these effects can either be due to the partially unfolding of the Trp28Ala mutant or to the absence of the indole side chain of Trp28 as possible interaction partner for the active site cysteines, ...

Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species Vrije Universiteit Brussel

Hui Wang, Soumaya Bouzakoura, Sven de Mey, Heng Jiang, Lun Law Ka, Inès Dufait, Cyril Corbet, Valeri Verovski, Thierry Gevaert, Olivier Feron, et al.

Auranofin (AF) is an anti-arthritic drug considered for combined chemotherapy due to its ability to impair the redox homeostasis in tumor cells. In this study, we asked whether AF may in addition radiosensitize tumor cells by targeting thioredoxin reductase (TrxR), a critical enzyme in the antioxidant defense system operating through the reductive protein thioredoxin. Our principal findings in murine 4T1 and EMT6 tumor cells are that AF at ...

The zinc center influences the redox and thermodynamic properties of Escherichia coli thioredoxin 2 Vrije Universiteit Brussel

Hayat El Hajjaji, Mireille Dumoulin, D. Colau, Goedele Roos, Joris Messens, Jean François Collet
Thioredoxins are small, ubiquitous redox enzymes that reduce protein disulfide bonds by using a pair of cysteine residues present in a strictly conserved WCGPC catalytic motif. The Escherichia coli cytoplasm contains two thioredoxins, Trx1 and Trx2. Trx2 is special because it is induced under oxidative stress conditions and it has an additional N-terminal zinc-binding domain. We have determined the redox potential of Trx2, the pK(a) of the ...

Plant NADPH-dependent thioredoxin reductases are crucial for the metabolism of sink leaves and plant acclimation to elevated CO2 Ghent University

Paulo V. L. Souza, Liang-Yu Hou, Hu Sun, Louis Poeker, Martin Lehman, Humaira Bahadar, Adilson P. Domingues-Junior, Avilien Dard, Laetitia Bariat, Jean-Philippe Reichheld, et al.
Plants contain three NADPH-thioredoxin reductases (NTR) located in the cytosol/mitochondria (NTRA/B) and the plastid (NTRC) with important metabolic functions. However, mutants deficient in all NTRs remained to be investigated. Here, we generated and characterised the triple Arabidopsis ntrabc mutant alongside with ntrc single and ntrab double mutants under different environmental conditions. Both ntrc and ntrabc mutants showed reduced growth ...

The conserved active site tryptophan of thioredoxine has no effect on its redox properties Vrije Universiteit Brussel

Goedele Roos
In Staphylococcus aureus thioredoxin (Trx) it has been shown that mutation of the conserved active site tryptophan residue (Trp28) has a large effect on the protein stability, on the pKa of the nucleophilic cysteine and on the redox potential. Since these effects can either be due to the partially unfolding of the Trp28Ala mutant or to the absence of the indole side chain of Trp28 as possible interaction partner for the active site cysteines, ...