The Human Thioredoxin System: Modifications and Clinical Applications

Document Type: Review Article

Author

Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

The thioredoxin system, comprising thioredoxin (Trx), thioredoxin reductase (TrxR) and NADPH, is one of the major cellular antioxidant systems, implicated in a large and growing number of biological functions. Trx acts as an oxidoreductase via a highly conserved dithiol/disulfide motif located in the active site ( Trp-Cys-Gly-Pro- Cys-Lys-). Different factors are involved in the regulation of Trx activity, including its expression level, localization, protein-protein interactions, post-translational modifications and some chemical inhibitors. Mammalian TrxRs are selenoproteins which have a –Cys-Val-Asn-Val-Gly-Cys- N-terminal active site, as well as a C-terminal selenium-containing active site. Besides two Cys-residues in the redox-regulatory domain of cytosolic Trx (Trx1), human Trx1 has three additional Cys-residues. Post-translational modifications of human Trx1 which are involved in the regulation of its activity can happen via modification of Cys-residues including thiol oxidation, glutathionylation and S-nitrosylation or via modification of other amino acid residues such as nitration of Tyr-49. Because of the numerous functions of the thioredoxin system, its inhibition (mainly happens via the targeting TrxR) can result in major cellular consequences, which are potentially pro-oxidant in nature, leading to cell death via necrosis or apoptosis if overexpression of Trx and other antioxidative enzymes can not recuperate cell response. Considering this feature, several anticancer drugs have been used which can inhibit TrxR. Elevated levels of Trx and/or TrxR have been reported in many different human malignancies, positively correlated with aggressive tumor growth and poor prognosis. Moreover, anti-oxidative and anti- apoptotic effects of Trx are reasons to study its clinical application as a drug.

Keywords


1. Holmgren A. Thioredoxin. Annu Rev Biochem 1985; 54:237-271.

2. Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Annu Rev Immunol 1997; 15:351-369.

3. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000 9; 408:239-247.

4. Holmgren A. Thioredoxin structure and mechanism: conformational changes on oxidation of the active-site sulfhydryls to a disulfide. Structure 1995; 3:239-243.

5. Laurent TC, Moore EC, Reichard P. Enzymatic synthesis of deoxyribonucleotides. Iv. Isolation and characterization of thioredoxin, the Hydrogen donor from escherichia Coli B. J Biol Chem 1964 ; 239:3436-3444.

6. Luthman M, Eriksson S, Holmgren A, Thelander L. Glutathione-dependent hydrogen donor system for calf thymus ribonucleoside-diphosphate reductase. Proc Natl Acad Sci U S A 1979; 76:2158-2162.

7. Welsh SJ, Bellamy WT, Briehl MM, Powis G. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 2002; 62:5089-5095.

8. Matthews JR, Wakasugi N, Virelizier JL, Yodoi J, Hay RT. Thioredoxin regulates the DNA binding activity of NF- kappa B by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res 1992; 20:3821-3830.

9. Abate C, Patel L, Rauscher FJ, 3rd, Curran T. Redox regulation of fos and jun DNA-binding activity in vitro. Science. 1990; 249:1157-1161.

10. Powis G, Kirkpatrick DL, Angulo M, Baker A. Thioredoxin redox control of cell growth and death and the effects of inhibitors. Chem Biol Interact 1998; 111-112:23-34.

11. Powis G, Montfort WR. Properties and biological activities of thioredoxins. Annu Rev Pharmacol Toxicol. 2001;41:261-95.

12. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. Embo J 1998; 17:2596-2606.

13. Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol 2000; 164:6287-6295.

14.Holmgren A. Thioredoxin. VI. The amino acid sequence of the protein from Escherichia coli B. Eur J Biochem 1968; 6:475-484.

15. Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem 1989; 264:13963-13966.

16.Eklund H, Gleason FK, Holmgren A. Structural and functional relations among thioredoxins of different species. Proteins 1991; 11:13-28.

17.Imamoto N, Kamei Y, Yoneda Y. Nuclear transport factors: function, behavior and interaction. Eur J Histochem 1998; 42:9-20.

18.Ueno M, Masutani H, Arai RJ, Yamauchi A, Hirota K, Sakai T, et al. Thioredoxin-dependent redox regulation of p53-mediated p21 activation. J Biol Chem 1999; 274:35809-35815.

19.Masutani H, Hirota K, Sasada T, Ueda-Taniguchi Y, Taniguchi Y, Sono H, et al. Transactivation of an inducible anti-oxidative stress protein, human thioredoxin by HTLV-I Tax. Immunol Lett 1996 ; 54:67-71.

20.Makino Y, Yoshikawa N, Okamoto K, Hirota K, Yodoi J, Makino I, et al. Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function. J Biol Chem 1999 29; 274:3182-3188.

21.Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, et al. Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. Embo J 1999; 18:1905-1914.

22.Maruyama T, Sachi Y, Furuke K, Kitaoka Y, Kanzaki H, Yoshimura Y, et al. Induction of thioredoxin, a redox- active protein, by ovarian steroid hormones during growth and differentiation of endometrial stromal cells in vitro. Endocrinology 1999; 140:365-3672.

23.Nakamura H, Bai J, Nishinaka Y, Ueda S, Sasada T, Ohshio G, et al. Expression of thioredoxin and glutaredoxin, redox-regulating proteins, in pancreatic cancer. Cancer Detect Prev 2000; 24:53-60.

24.Miranda-Vizuete A, Sadek CM, Jimenez A, Krause WJ, Sutovsky P, Oko R. The mammalian testis-specific thioredoxin system. Antioxid Redox Signal 2004; 6:25-40.

25.Tagaya Y, Maeda Y, Mitsui A, Kondo N, Matsui H, Hamuro J, et al. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. Embo J 1989; 8:757-764.

26.Rubartelli A, Bajetto A, Allavena G, Wollman E, Sitia R. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem 1992; 267:24161-24164.

27.Kishimoto C, Shioji K, Nakamura H, Nakayama Y, Yodoi J, Sasayama S. Serum thioredoxin (TRX) levels in patients with heart failure. Jpn Circ J 2001; 65:491-494.

28.Martinez-Pinna R, Lindholt JS, Blanco-Colio LM, Dejouvencel T, Madrigal-Matute J, Ramos-Mozo P, et al. Increased levels of thioredoxin in patients with abdominal aortic aneurysms (AAAs). A potential link of oxidative stress with AAA evolution. Atherosclerosis 2010; 212:333-338.

 29. Yamada Y, Nakamura H, Adachi T, Sannohe S, Oyamada H, Kayaba H, et al. Elevated serum levels of thioredoxin in patients with acute exacerbation of asthma. Immunol Lett 2003; 86:199-205.

30. Nakamura H, De Rosa S, Roederer M, Anderson MT, Dubs JG, Yodoi J, et al. Elevation of plasma thioredoxin levels in HIV-infected individuals. Int Immunol 1996; 8:603-611.

31. Yoshida S, Katoh T, Tetsuka T, Uno K, Matsui N, Okamoto T. Involvement of thioredoxin in rheumatoid arthritis: its costimulatory roles in the TNF-alpha-induced production of IL-6 and IL-8 from cultured synovial fibroblasts. J Immunol 1999; 163:351-358.

32. Kumagai S. [ADF/thioredoxin as an indicator of oxidative stress]. Rinsho Byori 1998 ; 46:574-580.

33. Kakisaka Y, Nakashima T, Sumida Y, Yoh T, Nakamura H, Yodoi J, et al. Elevation of serum thioredoxin levels in patients with type 2 diabetes. Horm Metab Res 2002; 34:160-164.

34. Leaver SK, MacCallum NS, Pingle V, Hacking MB, Quinlan GJ, Evans TW, et al. Increased plasma thioredoxin levels in patients with sepsis: positive association with macrophage migration inhibitory factor. Intensive Care Med 2010; 36:336-341.

35. Zhang XY, Chen da C, Xiu MH, Wang F, Qi LY, Sun HQ, et al. The novel oxidative stress marker thioredoxin is increased in first-episode schizophrenic patients. Schizophr Res 2009; 113:151-157.

36. Miyazaki K, Noda N, Okada S, Hagiwara Y, Miyata M, Sakurabayashi I, et al. Elevated serum level of thioredoxin in patients with hepatocellular carcinoma. Biotherapy 1998; 11:277-288.

37. Nakamura H, De Rosa SC, Yodoi J, Holmgren A, Ghezzi P, Herzenberg LA, et al. Chronic elevation of plasma thioredoxin: inhibition of chemotaxis and curtailment of life expect