ReviewThioredoxin reductase as a pharmacological target
Graphical Abstract
Introduction
The cytosolic and mitochondrial thioredoxin reductase (TrxR) and thioredoxins (Trx1 and Trx2) are critical components of the mammalian thioredoxin system [1]. Trx and TrxR provide a coupled redox system required for redox reactions in biosynthetic pathways involved in controlling redox homeostasis in cells [2], [3].
TrxRs are FAD-containing pyridine nucleotide disulfide oxidoreductases that utilize NADPH for reduction of active-site disulfide of Trxs. TrxR is necessary to all biochemical pathways in which Trx is involved as a reducing substrate [4].
Crucial redox-sensitive biological processes, including cell survival, growth, migration, and inhibition of apoptosis is mediated by thioredoxin system. However, the overexpression of TrxR and Trxs, as a defense response against oxidative stress, are also associated to several type of cancers through an unknown mechanism [4]. Moreover, TrxR plays also an important role in diverse physiological and pathological conditions such as parasitoses, chronic inflammatory, autoimmune diseases, and neurodegenerative disorders [5], [6], [7], [8], [9], [10], [11], [12], [13].
Rapid proliferation of cancer cells requires high metabolic activity, including increased glycolysis and other metabolic reactions [14]. Due to this increased metabolic rate, cancer cells, particularly those in advanced stages, are subject to high oxidative stress caused by abundant reactive oxygen species (ROS) production, which are considered to originate mainly from the electronic leakage of mitochondrial respiratory complexes [14], [15], [16].
Trx, a redox active protein, can be oxidized by ROS, which leads to the formation of a disulfide bridge (vide infra). The reduction by TrxR re-activates Trx providing a circuit for sequential turnover in multiple oxidation/reduction cycles [2], [17]. In its reduced form, Trx inhibits apoptosis signal-regulating kinase 1 (ASK1) and the downstream mitogen-activated protein kinase p38 (p38-MAPK). Upon accumulating ROS, Trx is oxidized, and ASK1 is activated, leading to apoptotic cell death [18], [19]. In several cancer cells, over-expression of Trx increases the capacity for ROS, which leads to increased drug resistance and promotes tumor progression [20]. Therefore, several small molecules targeting the Trx-TrxR system have been developed to preferentially induce cell death in malignant cells due to the increased dependence of these cells on the anti-oxidative activity of the Trx-TrxR system [21], [22].
Recently published reviews are mainly focused on the overactivation/dysfunction of TrxRs linked to the onset and development of cancer. These researchers also indicated that a number of effective natural and synthetic inhibitors of mammalian TrxRs could be used as potential anticancer agents [5], [23], [24], [25], [26], [27], [28], [29].
This review focuses on the most critical aspects of the cellular functions of TrxRs and their inhibition mechanisms through direct targeting to them or their substrates or protein interactors by metal ions or other chemicals. To update the involvement of overactivation/dysfunction of TrxRs in various pathological conditions, human diseases associated with TrxRs genes were critically summarized by publicly available genome-wide association study (GWAS) catalogs and literature. The evidence presented here justifies why TrxR is increasingly recognized as one of the most critical clinical targets, as well as the growing interest in developing molecules capable of interfering with the functions of TrxR enzymes.
Section snippets
Cellular functions of thioredoxin reductase (TrxRs) and thioredoxins (Trxs)
TrxR is a selenoprotein with three isozymes (TrxR1, TrxR2, and TrxR3, Table 1), vulnerable to low dietary selenium (Se) intakes, though less so than glutathione peroxidase-1 (Gpx-1), another crucial antioxidant enzyme in humans [30], [31], [32], [33], [34]. TrxR activity in the liver, kidneys, and lungs is decreased by Se deficiency and enhanced by high Se intake, while the activity of the enzyme in animal brains is much less affected by low Se intake because its concentrations in the brain are
Functions of reduced thioredoxin
Reduced Trx (which is regenerated by TrxR) has several different important roles [68]. It functions as one of the two alternatives reducing substrates for ribonucleotide reductase and is therefore important for DNA synthesis and repair [69]. Reduced glutaredoxin, which depends on GSH as a reducing cofactor for regeneration, is used by ribonucleotide reductase as a secondary alternative reducing substrate [70]. Therefore, it is especially unfavorable if both of the two parallel electron
Thioredoxin reductase inhibition by metals
TrxR is very sensitive to inhibition by several metals including gold, palladium, and platinum, as well as by silver, zinc, mercury, cadmium and gadolinium (Fig. 3) [86], [87], [88], [89], [90], [91].
While TrxR strongly binds particularly toxic metals, its substrate Trx is also a heavy metal-binding protein. This probably means that the substrate can help protect the enzyme itself from inhibition by the metal ion, when the total concentration of the latter is substantially lower than the
Thioredoxin reductase inhibition by other chemicals
A series of other chemicals can form covalent adducts to selenocysteine and cysteine residues of TrxR and Trx causing irreversible effects on their activity [145].
4-Hydroxynonenal and acrolein are formed as secondary products of peroxidation of polyunsaturated fatty acids. The peroxidation rate in vivo depends on the ratio of polyunsaturated to monounsaturated fatty acids in the diet [146], with dietary stearic acid having a similar but not equally strong effect as dietary linoleic acid because
TrxR protein interactors
TrxR may regulate signaling and metabolic pathways though its interaction with proteins, receptors and enzymes respectively. From this perspective, all the interactors of TrxR1, TrxR2 and TrxR3 deposited in the publicly available bioGRID protein-protein interaction (PPI) database (https://thebiogrid.org) [178] and reported in the literature were mined and presented in the Table 2. Interestingly, according to the recent reported human heavy metal proteome [179], 25% of the interactors of TrxR1
Association of thioredoxin reductase 1, 2, and 3 genes with human diseases
There are many reported associations between the TrxR genes and their variants with human diseases in GWAS (Genome-Wide Association Studies) catalogs and literature. TrxR1 (TXNRD1) gene is associated with nervous system diseases, including epilepsy [187], aura [188], cryptogenic and awakening epilepsy [187]), neoplasms (adenoma [189], mesothelioma [190], pancreatic cancer [191], trabecular, papillary, monomorphic, microcystic, basal cell and follicular thyroid adenomas [189]), skin and
Conclusion
The present review aims to carry out a critical reappraisal of the literature on the rationale of targeting TrxR for pharmaceutical purposes. TrxR is necessary to all biochemical pathways in which Trx is involved as a reducing substrate; those have been suggested to play roles in such diverse physiological and pathological conditions. There are two redox sites of TrxR: the first is constituted by the FAD and a couple of Cys residues that receives electrons from NADPH, and the second in the
CRediT authorship contribution statement
Geir Bjørklund: Conceptualization, Writing – original draft, Data curation, Visualization, Investigation, Writing – review & editing, Supervision, Project administration. Lili Zou: Data curation, Visualization, Investigation, Writing – review & editing Jun Wang: Data curation, Visualization, Investigation, Writing – review & editing. Christos T. Chasapis: Data curation, Visualization, Investigation, Writing – review & editing. Massimiliano Peana: Conceptualization, Writing – original draft,
Author contributions
All authors confirmed they have contributed to the intellectual content of this paper and have met the following three requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
LZ and JW thank the National Natural Science Foundation of China (32170191) for the financial support.
References (213)
- et al.
Thioredoxin glutathione reductase: its role in redox biology and potential as a target for drugs against neglected diseases
Biochim. Biophys. Acta
(2011) - et al.
Crystal structure of Plasmodium falciparum thioredoxin reductase, a validated drug target
Biochem. Biophys. Res. Commun.
(2012) - et al.
A model for manganese interaction with Deinococcus radiodurans proteome network involved in ROS response and defense
J. Trace Elem. Med. Biol.
(2018) - et al.
On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases
J. Inorg. Biochem.
(2012) - et al.
Targeting the thioredoxin system for cancer therapy
Trends Pharmacol. Sci.
(2017) - et al.
Selenium homeostasis and induction of thioredoxin reductase during long term selenite supplementation in the rat
J. Trace Elem. Med. Biol.
(2011) - et al.
TrxR1 and GPx2 are potently induced by isothiocyanates and selenium, and mutually cooperate to protect Caco-2 cells against free radical-mediated cell death
Biochim. Biophys. Acta
(2012) - et al.
Selenocysteine in mammalian thioredoxin reductase and application of ebselen as a therapeutic
Free Radic. Biol. Med.
(2018) - et al.
Effect of selenium on rat thioredoxin reductase activity: increase by supranutritional selenium and decrease by selenium deficiency
Biochem. Pharmacol.
(1999) - et al.
The antioxidant role of selenium and seleno-compounds
Biomed. Pharmacother.
(2003)
Correcting a marginal riboflavin deficiency improves hematologic status in young women in the United Kingdom (RIBOFEM)
Am. J. Clin. Nutr.
Focus on mammalian thioredoxin reductases — important selenoproteins with versatile functions
Biochim. Biophys. Acta
Crystal structure and catalysis of the selenoprotein thioredoxin reductase 1
J. Biol. Chem.
Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors
Free Radic. Biol. Med.
Reversible oxidation of mitochondrial peroxiredoxin 3 in mouse heart subjected to ischemia and reperfusion
FEBS Lett.
Laminar shear stress up-regulates peroxiredoxins (PRX) in endothelial cells: PRX 1 as a mechanosensitive antioxidant
J. Biol. Chem.
A novel antioxidant mechanism of ebselen involving ebselen diselenide, a substrate of mammalian thioredoxin and thioredoxin reductase
J. Biol. Chem.
Ebselen: a thioredoxin reductase-dependent catalyst for alpha-tocopherol quinone reduction
Toxicol. Appl. Pharmacol.
Metabolism of selenium compounds catalyzed by the mammalian selenoprotein thioredoxin reductase
Biochim. Biophys. Acta
Regulation of the catalytic activity and structure of human thioredoxin 1 via oxidation and S-nitrosylation of cysteine residues
J. Biol. Chem.
Redox potential of human thioredoxin 1 and identification of a second dithiol/disulfide motif
J. Biol. Chem.
Thioredoxin 1 is inactivated due to oxidation induced by peroxiredoxin under oxidative stress and reactivated by the glutaredoxin system
J. Biol. Chem.
Redox regulation in the lens
Prog. Retin. Eye Res.
Implications of the mitochondrial interactome of mammalian thioredoxin 2 for normal cellular function and disease
Free Radic. Biol. Med.
Both thioredoxin 2 and glutaredoxin 2 contribute to the reduction of the mitochondrial 2-Cys peroxiredoxin Prx3
J. Biol. Chem.
Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite
Biochim. Biophys. Acta
Oxidation of active center cysteine of bovine 1-Cys peroxiredoxin to the cysteine sulfenic acid form by peroxide and peroxynitrite
Free Radic. Biol. Med.
Base excision DNA repair defect in thioredoxin-1 (Trx1)-deficient cells
Mutat. Res.
Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA
Mol. Asp. Med.
The Drosophila homolog of methionine sulfoxide reductase A extends lifespan and increases nuclear localization of FOXO
FEBS Lett.
Methionine sulfoxide reductase B in the endoplasmic reticulum is critical for stress resistance and aging in Drosophila
Biochem. Biophys. Res. Commun.
Activation of spleen tyrosine kinase is required for TNF-α-induced endothelin-1 upregulation in human aortic endothelial cells
FEBS Lett.
Noble metal targeting of thioredoxin reductase--covalent complexes with thioredoxin and thioredoxin-related protein of 14 kDa triggered by cisplatin
Free Radic. Biol. Med.
Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity
J. Biol. Chem.
Effect of mercury(II) on Nrf2, thioredoxin reductase-1 and thioredoxin-1 in human monocytes
Dent. Mater.
Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase
Free Radic. Biol. Med.
Inhibition of the thioredoxin system in the brain and liver of zebra-seabreams exposed to waterborne methylmercury
Toxicol. Appl. Pharmacol.
Thioredoxin reductase: a target for gold compounds acting as potential anticancer drugs
Coord. Chem. Rev.
Human placenta thioredoxin reductase. Isolation of the selenoenzyme, steady state kinetics, and inhibition by therapeutic gold compounds
J. Biol. Chem.
Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1)
Toxicol. Vitr. Int. J. Publ. Assoc. BIBRA
Repurposing of auranofin: thioredoxin reductase remains a primary target of the drug
Biochimie
Noble metals in medicine: Latest advances
Coord. Chem. Rev.
Conditional expression of 15-lipoxygenase-1 inhibits the selenoenzyme thioredoxin reductase: modulation of selenoproteins by lipoxygenase enzymes
J. Biol. Chem.
Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system
Antioxid. Redox Signal.
The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants
Int. J. Cancer
Redox active disulfides: the thioredoxin system as a drug target
Oncol. Res.
Thioredoxin reductase and its inhibitors
Curr. Protein Pept. Sci.
Thioredoxin reductase inhibitors: updated patent review (2017-present)
Expert Opin. Ther. Pat.
Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy
Mol. Nutr. Food Res.
Selenium and the selenoprotein thioredoxin reductase in the prevention, treatment and diagnostics of cancer
Antioxid. Redox Signal.
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