Elsevier

Free Radical Biology and Medicine

Volume 66, 8 January 2014, Pages 75-87
Free Radical Biology and Medicine

Review Article
The thioredoxin antioxidant system

https://doi.org/10.1016/j.freeradbiomed.2013.07.036Get rights and content

Highlights

  • Thioredoxin- or glutathione-dependent peroxidases are major antioxidant enzymes.

  • Mammalian thioredoxin and glutathione systems cancross-talk.

  • Bacteria thioredoxin reductase is different than mammalian thioredoxin reductase.

  • Some pathogenic bacteria lack a glutathione system.

  • Bacterial thioredoxin system emerges as a novel antibiotic target.

Abstract

The thioredoxin (Trx) system, which is composed of NADPH, thioredoxin reductase (TrxR), and thioredoxin, is a key antioxidant system in defense against oxidative stress through its disulfide reductase activity regulating protein dithiol/disulfide balance. The Trx system provides the electrons to thiol-dependent peroxidases (peroxiredoxins) to remove reactive oxygen and nitrogen species with a fast reaction rate. Trx antioxidant functions are also shown by involvement in DNA and protein repair by reducing ribonucleotide reductase, methionine sulfoxide reductases, and regulating the activity of many redox-sensitive transcription factors. Moreover, Trx systems play critical roles in the immune response, virus infection, and cell death via interaction with thioredoxin-interacting protein. In mammalian cells, the cytosolic and mitochondrial Trx systems, in which TrxRs are high molecular weight selenoenzymes, together with the glutathione-glutaredoxin (Grx) system (NADPH, glutathione reductase, GSH, and Grx) control the cellular redox environment. Recently mammalian thioredoxin and glutathione systems have been found to be able to provide the electrons crossly and to serve as a backup system for each other. In contrast, bacteria TrxRs are low molecular weight enzymes with a structure and reaction mechanism distinct from mammalian TrxR. Many bacterial species possess specific thiol-dependent antioxidant systems, and the significance of the Trx system in the defense against oxidative stress is different. Particularly, the absence of a GSH-Grx system in some pathogenic bacteria such as Helicobacter pylori, Mycobacterium tuberculosis, and Staphylococcus aureus makes the bacterial Trx system essential for survival under oxidative stress. This provides an opportunity to kill these bacteria by targeting the TrxR-Trx system.

Graphical abstract

Lacking of glutathione system in some pathogenic bacteria makes the bacterial Trx system emerge as an antibiotic drug target

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Introduction

The thioredoxin system, comprising NADPH, thioredoxin reductase (TrxR), and thioredoxin (Trx), is a major disulfide reductase system which can provide electrons to a large range of enzymes and is found to be critical for DNA synthesis and defense against oxidative stress. Trx was originally discovered to be a reducing substrate of ribonucleotide reductase (RNR) [1], the essential enzyme catalyzing de novo synthesis of 2′-deoxyribonucleotides from corresponding ribonucleotides and is thus involved in DNA replication and repair (reviewed recently in [2]). In this review we will focus on the roles of the thioredoxin system as antioxidant in the defense against oxidative stress.

Section snippets

Structure and reaction mechanism of Trx and TrxR

Thioredoxins are typically 12 kDa small reductases, catalyzing protein disulfide/dithiol change with a conserved -CGPC- active site motif. Trx is ubiquitously distributed from archaea, bacteria to man. The structure of Trx is that five β-strands form the internal core of protein, and four α-helices and a short stretch of helix surround the central β-sheets. The active site disulfide is located after the β2-sheet and forms the N-terminal portion of α2 [3]. Many critical enzymes in the

Antioxidant roles of the Trx system

In mammalian cells there are two major thiol-dependent antioxidant systems, the Trx and the glutathione antioxidant system. GSH is the most abundant nonprotein thiol in the mammalian cells. Mammalian cells possess two Trx systems, the cytosolic Trx1 and the mitochondrial Trx2 system (Fig. 3). Trx2 has only the two cysteines in its active site, whereas Trx1 has three additional extra cysteines, which play a role in the redox regulation of activity and NO signaling [15].

The antioxidant activity

Thioredoxin antioxidant systems in bacteria

Since bacteria live in various environments, different bacteria are equipped with various types of antioxidant systems [84]. The thiol-dependent peroxidases include bacterioferritin comigratory protein (BCP), thiol peroxidase (Tpx), and AhpC [84]. AhpC is classified as 2-Cys Prx with conserved N-terminal peroxidatic CysP and C-terminal resolving CysR and widely distributed from prokaryote to eukaryotes with a high catalytic efficiency, e.g.,>107 M−1 s−1 in Salmonella typhimurium [85] (Fig. 5).

Conclusions

In summary, organisms are equipped with a diversity of thiol-dependent antioxidant systems, which coordinate removal of reactive oxygen and nitrogen species. The significance of Trx systems in protecting the cells against oxidative stress in different organisms varies. In mammalian cells Trx and GSH-Grx systems can act as a backup system for each other. In many pathogenic bacteria the GSH system is lacking, which confers on the thioredoxin system an essential role for growth and survival under

Acknowledgments

The authors acknowledge support from the Swedish Research Council Medicine (3529), the Swedish Cancer Society (961), the K.A. Wallenberg Foundation, Åke Wiberg Stiftelse, and the Karolinska Institutet.

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