Thioredoxin Reductase

Abstract

Thioredoxin reductase TrxR, EC 1.6.4.5 is a homodimeric flavoenzyme that catalyzed the reduction of the thioredoxin Trx . It has been characterized in many bacteria and mammalian organism and categorized under two different types: bacterial and mammalian. Mammalian TrxRs contain an essential selenocysteine residue in the conserved C-terminal sequence. Mammalian TrxRs have three isoforms; cytosolic, mitochondrial and testis-specific. TrxR3, as testis-specific form, have different property than the other mammalian TrxRs. TrxR is involved in many cellular functions including DNA synthesis, redox signaling, antioxidative defence, selenium metabolism and regulation of apoptosis. Because of the many known functions, it is not surprising that this enzyme is a major subject of the many research. TrxR has been purified and characterized from a wide variety of species by using ion-exchange and affinity chromatographies. Notably, TrxR is a target enzyme for cancer drug research due to the relation with apoptosis. In this review we will present the intra- and extracellular biochemical functions of the enzyme and important medical applications in drug development.

Keywords

• Thioredoxin reductase,Molecular Structure,biochemical function,clinical importance

Tiyoredoksin Redüktaz

Abstract

Tiyoredoksin redüktaz tiyoredoksinin indirgenmesini katalizleyen homodimerik bir flavoenzimdir. Enzim birçok organizmada karakterize edilmiş ve bakteri ve memeli olmak üzere iki sınıfta toplanmıştır. Memeli TrxR C-ucu aminoasit dizisinde selenosistein içerir. Sitozolde, mitokondride ve testiste olmak üzere memeli TrxR’ nin üç izoformu bulunur. TrxR’ nin DNA sentezi, redoks sinyali, antioksidatif savunma, selenyum metabolizması ve apoptozun düzenlenmesinde önemli fonksiyonları vardır. Bu nedenle birçok araştırmaya konu olmaktadır. TrxR iyon değiştirici ve afinite kromatografileri kullanılarak çeşitli türlerden saflaştırılmış ve karakterize edilmiştir. Özellikle apoptozdaki fonksiyonundan dolayı kanser araştırmaları için hedef proteindir. Bu derlemede, enzimin hücre içi ve dışındaki biyokimyasal fonksiyonları ve ilaç geliştirme alanındaki medikal önemi sunulmaktadır

Keywords

• Tiyoredoksin redüktaz,moleküler yapı,biyokimyasal fonksiyon ve klinik önemi

References

1. [1] C.H. Williams, L.D. Arscott, S. Müller, B.W. Lennon, M.L. Ludwig, P.F. Wang, D.M. Veine, K. Becker, R.H. Schirmer, Thioredoxin reductase two modes of catalysis have evolved. Eur. J. Biochem., 267 (2000) 6110.
2. [2] P. Zagrodzki, Thioredoxin reductase--a new target for molecular medical investigations, Postepy. Hig. Med. Dosw., 56 (2002) 155.
3. [3] E.S. Arner, A. Holmgren, The thioredoxin system in cancer, Semin. Cancer Biol., 16 (2006) 420.
4. [4] E.S. Arner, A. Holmgren, Physiological functions of thioredoxin and thioredoxin reductase. Eur. J. Biochem., 267 (2000) 6102.
5. [5] D. Mustacich, G. Powis, Thioredoxin reductase. Biochem. J., 346 (2000) 1.
6. [6] B. Rozell, A. Holmgren, H.A. Hansson, Ultrastructural demonstration of thioredoxin and thioredoxin reductase in rat hepatocytes. Eur. J. Cell Biol., 46 (1988) 470.
7. [7] Q.A. Sun, L. Kirnarsky, S. Sherman, V.N. Gladyshev, Selenoprotein oxidoreductase with specificity for thioredoxin and glutathione systems. Proc. Natl. Acad. Sci. USA, 98 (2001) 3673.
8. [8] S. Urig, K. Becker, On the potential of thioredoxin reductase inhibitors for cancer therapy, Semin. Cancer Biol., 16 (2006) 452.

9. [9] A. Argyrou, J.S. Blanchard, Flavoprotein disulfide reductases: advances in chemistry and function Prog Nucleic Acid Res. Mol. Biol., 78 (2004) 89.
10. [10] K. Anestal, E.S. Arner, Rapid induction of cell death by selenium-compromised thioredoxin reductase 1 but not by the fully active enzyme containing selenocysteine, J. Biol. Chem., 278 (2003) 15966.
11. [11] G. Maggioli, L. Piacenza, B. Carambula, C. Carmona, Purification, characterization, and immunolocalization of a thioredoxin reductase from adult Fasciola hepatica, J. Parasitol., 90 (2004) 205.
12. [12] N.N. Ulusu, B. Tandoğan, Purification and kinetic properties of glutathione reductase from bovine liver. Mol. Cell. Biochem., 303 (2007) 45.
13. [13] B. Tandogan, N.N. Ulusu, Purification and Kinetics of Bovine Kidney Cortex Glutathione Reductase. Protein Pept Lett., 17 (2010) 667.
14. [14] M.L. Speranza, S. Ronchi, L. Minchiotti, Purification and characterization of yeast thioredoxin reductase. Biochim. Biophys. Acta., 327 (1973) 274.
15. [15] H. Bauer, V. Massey, L.D. Arscott, R.H. Schirmer, D.P. Ballou, C.H. Williams Jr., The mechanism of high Mr thioredoxin reductase from Drosophila melanogaster, J. Biol. Chem., 278 (2003) 33020.
16. [16] T.W. Gilberger, B. Bergmann, R.D. Walter, S. Müller, The role of the C-terminus for catalysis of the large thioredoxin reductase from Plasmodium falciparum. FEBS Lett., 425 (1998) 407.
17. [17] Z. Cheng, L.D. Arscott, D.P. Ballou, C.H. Williams Jr., The relationship of the redox potentials of thioredoxin and thioredoxin reductase from Drosophila melanogaster to the enzymatic mechanism: reduced thioredoxin is the reductant of glutathione in Drosophila, Biochemistry, 46 (2007) 7875.
18. [18] E.S. Arner, L. Zhong, A. Holmgren, Preparation and assay of mammalian thioredoxin and thioredoxin reductase, Methods Enzymol., 300 (1999) 226.
19. [19] A. Holmgren, C. Lyckeborg, Enzymatic reduction of alloxan by thioredoxin and NADPH-thioredoxin reductase, Proc. Natl. Acad. Sci. USA. 77 (1980) 5149.
20. [20] J.M. May, S. Mendiratta, K.E. Hill, R.F. Burk, Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase, J. Biol. Chem., 272 (1977) 22607.
21. [21] M. Bjornstedt, S. Kumar, A. Holmgren, Selenodiglutathione is a highly efficient oxidant of reduced thioredoxin and a substrate for mammalian thioredoxin reductase, J. Biol. Chem., 267 (1992) 8030.
22. [22] G.E. Arteel, K. Briviba, H. Sies, Function of thioredoxin reductase as a peroxynitrite reductase using selenocysteine or ebselen, Chem. Res. Toxicol., 12 (1999) 264.
23. [23] D. Nikitovic, A. Holmgren, S-nitrosoglutathione is cleaved by the thioredoxin system with liberation of glutathione and redox regulating nitric oxide, J. Biol. Chem., 271 (1996) 19180.
24. [24] S. Gromer, J.H. Gross, Methylseleninate is a substrate rather than an inhibitor of mammalian thioredoxin reductase. Implications for the antitumor effects of selenium, J. Biol. Chem., 277 (2002) 9701.
25. [25] A. Holmgren, Thioredoxin and glutaredoxin systems, J. Biol. Chem., 264 (1989) 13963.
26. [26] A. Koc, C.K. Mathews, L.J. Wheeler, M.K. Gross, G.H. Merrill, Thioredoxin is required for deoxyribonucleotide pool maintenance during S phase, J. Biol. Chem., 281 (2006) 15058.
27. [27] J.M. May, C.E. Cobb, S. Mendiratta, K.E. Hill, R.F. Burk, Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase, J. Biol. Chem., 273 (1998) 23039.
28. [28] T. Nordman, L. Xia, L. Björkhem-Bergman, A. Damdimopoulos, I. Nalvarte, E.S. Arner, G. Spyrou, L.C. Eriksson, M. Björnstedt, J.M., Olsson, Regeneration of the antioxidant ubiquinol by lipoamide dehydrogenase, thioredoxin reductase and glutathione reductase, Biofactors, 18 (2003) 45.
29. [29] E.S. Arner, J. Nordberg, A. Holmgren, Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase, Biochem. Biophys. Res. Commun., 225 (1996) 268.
30. [30] S. Adler, P. Modrich, T7-induced DNA polymerase. Requirement for thioredoxin sulfhydryl groups, J. Biol. Chem., 258 (1983) 6956.
31. [31] A. Mukherjee, S.G. Martin, The thioredoxin system: a key target in tumour and endothelial cells, Br. J. Radiol., 81 (2008) 57.
32. [32] H. Schenk, M. Klein, W. Erdbrügger, W. Dröge, K. Schulze-Osthoff, Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1, Proc. Natl. Acad. Sci. USA, 91 (1994) 1672.
33. [33] P.B. Cassidy, K. Edes, C.C. Nelson, K. Parsawar, F.A. Fitzpatrick, P.J. Moos, Thioredoxin reductase is required for the inactivation of tumor suppressor p53 and for apoptosis induced by endogenous electrophiles, Carcinogenesis, 27 (2006) 2538.
34. [34] C. Biguet, N. Wakasugi, Z. Mishal, A. Holmgren, S. Chouaib, T. Tursz, H. Wakasugi, Thioredoxin increases the proliferation of human B-cell lines through a protein kinase C-dependent mechanism, J. Biol. Chem., 269 (1994) 28865.
35. [35] L. Zhong, A. Holmgren, Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations, J. Biol. Chem., 275 (2000) 18121.
36. [36] J. Nordberg, E.S. Arner, Reactive oxygen species, antioxidants, and the mammalian thioredoxin system, Free Radic. Biol. Med., 31 (2001) 1287.
37. [37] K.F. Tonissen, G. Di Trapani, Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy, Mol. Nutr. Food Res., 53 (2009) 87.
38. [38] Z. Liu, Z.Y. Du, Z.S. Huang, K.S. Lee, L.Q. Gu, Inhibition of thioredoxin reductase by curcumin analogs, Biosci. Biotechnol. Biochem., 72 (2008) 2214.
39. [39] J. Nordberg, L. Zhong, A. Holmgren, E.S. Arner, Mammalian thioredoxin reductase is irreversibly inhibited by dinitrohalobenzenes by alkylation of both the redox active selenocysteine and its neighboring cysteine residue, J. Biol. Chem., 273 (1998) 10835.
40. [40] B.L. Mau, G. Powis, Mechanism-based inhibition of thioredoxin reductase by antitumor quinoid compounds, Biochem. Pharmacol., 43 (1992) 1613.
41. [41] B. Tandoğan, N.N. Ulusu, The inhibition kinetics of yeast glutathione reductase by some metal ions, J. Enzyme Inhib. Med. Chem., 22 (2007) 489.
42. [42] M. Luthman, A. Holmgren, Rat liver thioredoxin and thioredoxin reductase: Purification and characterization, Biochemistry, 21 (1982) 6628.
43. [43] A. Holmgren, Bovine thioredoxin system. Purification of thioredoxin reductase from calf liver and thymus and studies of its function in disulfide reduction, J. Biol. Chem., 252 (1977) 4600.
44. [44] S. Watabe, Y. Makino, K. Ogawa, T. Hiroi, Y. Yamamoto, S.Y. Takahashi, Mitochondrial thioredoxin reductase in bovine adrenal cortex its purification, properties, nucleotide/amino acid sequences, and identification of selenocysteine, Eur. J. Biochem., 264 (1999) 74.
45. [45] V.P. Pigiet, R.R. Conley, Purification of thioredoxin, thioredoxin reductase, and glutathione reductase by affinity chromatography, J. Biol. Chem., 252 (1977) 6367.
46. [46] M.P. Rigobello, M.T. Callegaro, E. Barzon, M. Benetti, A. Bindoli, Purification of mitochondrial thioredoxin reductase and its involvement in the redox regulation of membrane permeability, Free Radic. Biol. Med., 24 (1998) 370.
47. [47] E. Tuncay, A.A. Seymen, E. Tanriverdi, N. Yaras, B. Tandogan, N.N. Ulusu, B. Turan, Gender related differential effects of Omega-3E treatment on diabetes-induced left ventricular dysfunction, Mol. Cell Biochem., 304 (2007) 255.
48. [48] D. Hagg, M.C. Englund, M. Jernas, C. Schmidt, O. Wiklund, L.M. Hulten, B.G. Ohlsson, L.M. Carlsson, B. Carlsson, P.A. Svensson, Oxidized LDL induces a coordinated up-regulation of the glutathione and thioredoxin systems in human macrophages, Atherosclerosis, 185 (2006) 282.
49. [49] Y. Kabuyama, T. Kitamura, J. Yamaki, M.K. Homma, S. Kikuchi, Y. Homma, Involvement of thioredoxin reductase 1 in the regulation of redox balance and viability of rheumatoid synovial cells, Biochem. Biophys. Res. Commun., 367 (2008) 491.
50. [50] H. Lemarechal, Y. Allanore, C. Chenevier-Gobeaux, O.G. Ekindjian, A. Kahan, D. Borderie, High redox thioredoxin but low thioredoxin reductase activities in the serum of patients with rheumatoid arthritis, Clin. Chim. Acta, 367 (2006) 156.
51. [51] Z.F. Peng, L.X. Lan, F. Zhao, J. Li, Q. Tan, H.W. Yin, H.H. Zeng, A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells, J. Zhejiang Univ. Sci. B, 9 (2008) 16.
52. [52] A.L. Simons, A.D. Parsons, K.A. Foster, K.P. Orcutt, M.A. Fath, D.R. Spitz, Inhibition of glutathione and thioredoxin metabolism enhances sensitivity to perifosine in head and neck cancer cells, J. Oncol., 2009 (2009) 519.
53. [53] N.N. Ulusu, B. Tandogan, M.A. Turkoglu, S. Demirer, Is it Useful to Determine Glutathione Peroxidase and Thioredoxin Reductase Activities for Comparisons of Malign and Benign Breast Diseases?, Turk. J. Biochem., 34 (2009) 187.
54. [54] M. Honeggar, R. Beck, P.J. Moos, Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity. Toxicol. Appl. Pharmacol., 241 (2009) 348.
55. [55] M.H. Yoo, X.M. Xu, B.A. Carlson, A.D. Patterson, V.N. Gladyshev, D.L. Hatfield, Targeting thioredoxin reductase 1 reduction in cancer cells inhibits selfsufficient growth and DNA replication, PLoS ONE, 2 (2007) e1112.