Review ArticleThe thioredoxin antioxidant system
Graphical abstract
Lacking of glutathione system in some pathogenic bacteria makes the bacterial Trx system emerge as an antibiotic drug target.
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.
References (146)
- et al.
The use of thiols by ribonucleotide reductase
Free Radic. Biol. Med.
(2010) - et al.
Structure, mechanism and regulation of peroxiredoxins
Trends Biochem. Sci.
(2003) - et al.
Structure analysis and molecular model of the selenoenzyme glutathione peroxidase at 2.8A resolution
J. Mol. Biol.
(1979) - et al.
Flavoprotein disulfide reductases: advances in chemistry and function
Prog. Nucleic Acid Res. Mol. Biol.
(2004) - et al.
Selenoproteins
J. Biol. Chem.
(2009) - et al.
Crystal structure and catalysis of the selenoprotein thioredoxin reductase 1
J. Biol. Chem.
(2009) - et al.
Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations
J. Biol. Chem
(2000) - et al.
Metabolism of selenium compounds catalyzed by the mammalian selenoprotein thioredoxin reductase
Biochim. Biophys. Acta
(2009) - et al.
Thioredoxin-dependent peroxide reductase from yeast
J. Biol. Chem.
(1994) - et al.
Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides
J. Biol. Chem.
(2012)
Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling
Free Radic. Biol. Med.
The peroxidase and peroxynitrite reductase activity of human erythrocyte peroxiredoxin 2
Arch. Biochem. Biophys.
Reactions of yeast thioredoxin peroxidases I and II with hydrogen peroxide and peroxynitrite: rate constants by competitive kinetics
Free Radic. Biol. Med.
Thiol chemistry and specificity in redox signaling
Free Radic. Biol. Med.
Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide
Free Radic. Biol. Med.
Structural evidence that peroxiredoxin catalytic power is based on transition-state stabilization
J. Mol. Biol.
Role of glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase in the reduction of lysophospholipid hydroperoxides
Free Radic. Biol. Med.
A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase
J. Biol. Chem.
Mechanisms of catalase activity of heme peroxidases
Arch. Biochem. Biophys.
2-Cys peroxiredoxin function in intracellular signal transduction: therapeutic implications
Trends Mol. Med.
Thioredoxin as a reducing agent for mammalian methionine sulfoxide reductases B lacking resolving cysteine
Biochem. Biophys. Res. Commun.
Functions and evolution of selenoprotein methionine sulfoxide reductases
Biochim. Biophys. Acta
Thioredoxin and thioredoxin reductase: current research with special reference to human disease
Biochem. Biophys. Res. Commun.
Tissue-specific functions of individual glutathione peroxidases
Free Radic. Biol. Med.
Glutaredoxin systems
Biochim. Biophys. Acta
Thioredoxin reductase-1 knock down does not result in thioredoxin-1 oxidation
Biochem. Biophys. Res. Commun.
Disruption of the mitochondrial thioredoxin system as a cell death mechanism of cationic triphenylmethanes
Free Radic. Biol. Med.
Glutathione and glutaredoxin act as a backup of human thioredoxin reductase 1 to reduce thioredoxin 1 preventing cell death by aurothioglucose
J. Biol. Chem
The thioredoxin-thioredoxin reductase system can function in vivo as an alternative system to reduce oxidized glutathione in Saccharomyces cerevisiae
J. Biol. Chem.
Human mitochondrial glutaredoxin reduces S-glutathionylated proteins with high affinity accepting electrons from either glutathione or thioredoxin reductase
J. Biol. Chem
Both thioredoxin 2 and glutaredoxin 2 contribute to the reduction of the mitochondrial 2-Cys peroxiredoxin Prx3
J. Biol. Chem.
Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation
J. Biol. Chem.
Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor
J. Biol. Chem.
Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1as a negative regulator of thioredoxin function and expression
J. Biol. Chem.
The interaction of thioredoxin with Txnip—evidence for formation of a mixed disulfide by disulfide exchange
J. Biol. Chem.
Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein
J. Biol. Chem.
Overexpression of thioredoxin-binding protein 2 increases oxidation sensitivity and apoptosis in human lens epithelial cells
Free Radic. Biol. Med.
A redox-dependent pathway for regulating class IIHDACs and cardiac hypertrophy
Cell
Thioredoxin-interacting protein (Txnip) is a critical regulator of hepatic glucose production
J. Biol. Chem.
Thioredoxin regulates adipogenesis through thioredoxin-interacting protein (Txnip) protein stability
J. Biol. Chem.
Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress
Blood
Thioredoxin-interacting protein mediates ER stress-induced beta cell death through initiation of the inflammasome
Cell Metab.
Focus on mammalian thioredoxin reductases—important selenoproteins with versatile functions
Biochim. Biophys. Acta
Inhibition of glutathione synthesis eliminates the adaptive response of ascitic hepatoma 22 cells to nedaplatin that targets thioredoxin reductase
Toxicol. Appl. Pharmacol.
Why do bacteria use so many enzymes to scavenge hydrogen peroxide?
Arch. Biochem. Biophys
Protein levels of Escherichia coli thioredoxins and glutaredoxins and their relation to null mutants, growth phase, and function
J. Biol. Chem.
Catalytic mechanism of thiol peroxidase from Escherichia coli. Sulfenic acid formation and overoxidation of essential CYS61
J. Biol. Chem.
Thioredoxin-dependent hydroperoxide peroxidase activity of bacterioferritin comigratory protein (BCP) as a new member of the thiol-specific antioxidant protein (TSA)/Alkyl hydroperoxide peroxidase C (AhpC) family
J. Biol. Chem
The role of the thioredoxin and glutaredoxin pathways in reducing protein disulfide bonds in the Escherichia coli cytoplasm
J. Biol. Chem.
Thioredoxin 2 is involved in the oxidative stress response in Escherichia coli
J. Biol. Chem.
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