Skip to main content Accessibility help

Differential inhibition of high and low Mr thioredoxin reductases of parasites by organotelluriums supports the concept that low Mr thioredoxin reductases are good drug targets

  • P. J. McMILLAN (a1), E. M. PATZEWITZ (a1), S. E. YOUNG (a1), G. D. WESTROP (a2), G. H. COOMBS (a2), L. ENGMAN (a3) and S. MÜLLER (a1)...


Thioredoxin reductase (TrxR), a NADPH-dependent disulfide oxidoreductase, is vital in numerous cellular processes including defence against reactive oxygen species, cell proliferation and signal transduction. TrxRs occur in 2 forms, a high Mr enzyme characterized by those of mammals, the malaria parasite Plasmodium falciparum and some worms, and a low Mr form is present in bacteria, fungi, plants and some protozoan parasites. Our hypothesis is that the differences between the forms can be exploited in the development of selective inhibitors. In this study, cyclodextrin- and sulfonic acid-derived organotelluriums known to inhibit mammalian TrxR were investigated for their relative efficacy against P. falciparum TrxR (PfTrxR), a high Mr enzyme, and Trichomonas vaginalis TrxR (TvTrxR), a low Mr form of TrxR. The results suggest that selective inhibition of low Mr TrxRs is a feasible goal.


Corresponding author

*Corresponding author: Division of Infection and Immunity and Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, UK. Tel: (+)44 141 330 2383. Fax: (+) 44 141 330 4600. E-mail:


Hide All
Andricopulo, A. D., Akoachere, M. B., Krogh, R., Nickel, C., McLeish, M. J., Kenyon, G. L., Arscott, L. D., Williams, C. H. Jr., Davioud-Charvet, E. and Becker, K. (2006). Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. Bioorganic & Medicinal Chemistry Letters 16, 22832292.
Arner, E. S. and Holmgren, A. (2006). The thioredoxin system in cancer. Seminars in Cancer Biology 16, 420426.
Baier, M. and Dietz, K. J. (2005). Chloroplasts as source and target of cellular redox regulation: a discussion on chloroplast redox signals in the context of plant physiology. Journal of Experimental Botany 56, 14491462.
Becker, K., Gromer, S., Schirmer, R. H. and Müller, S. (2000). Thioredoxin reductase as a pathophysiological factor and drug target. European Journal of Biochemistry 267, 61186125.
Brodsky, M., Yosef, S., Galit, R., Albeck, M., Longo, D. L., Albeck, A. and Sredni, B. (2007). The synthetic tellurium compound, AS101, is a novel inhibitor of IL-1beta converting enzyme. Journal of Interferon and Cytokine Research 27, 453462.
Carlton, J. M., Hirt, R. P., Silva, J. C. et al. (2007). Draft genome sequence of the sexually transmitted pathogen Trichomonas vaginalis. Science 315, 207212.
Coombs, G. H., Westrop, G. D., Suchan, P., Puzova, G., Hirt, R. P., Embley, T. M., Mottram, J. C. and Müller, S. (2004). The amitochondriate eukaryote Trichomonas vaginalis contains a divergent thioredoxin-linked peroxiredoxin antioxidant system. Journal of Biological Chemistry 279, 52495256.
Engman, L., McNaughton, M., Gajewska, M., Kumar, S., Birmingham, A. and Powis, G. (2006). Thioredoxin reductase and cancer cell growth inhibition by organogold(III) compounds. Anticancer Drugs 17, 539544.
Engman, L., Al-Maharik, N., McNaughton, M., Birmingham, A. and Powis, G. (2003 a). Thioredoxin reductase and cancer cell growth inhibition by organotellurium compounds that could be selectively incorporated into tumor cells. Bioorganic & Medicinal Chemistry Letters 11, 50915100.
Engman, L., Al-Maharik, N., McNaughton, M., Birmingham, A. and Powis, G. (2003 b). Thioredoxin reductase and cancer cell growth inhibition by organotellurium antioxidants. Anticancer Drugs 14, 153161.
Engman, L., Kandra, T., Gallegos, A., Williams, R. and Powis, G. (2000). Water soluble organotellurium compounds inhibit thioredoxin reductase and the growth of human cancer cells. Anticancer Drug Design 15, 323330.
Fidock, D. A., Nomura, T. and Wellems, T. E. (1998). Cycloguanil and its parent compound proguanil demonstrate distinct activities against Plasmodium falciparum malaria parasites transformed with human dihydrofolate reductase. Molecular Pharmacology 54, 11401147.
Gilberger, T. W., Schirmer, R. H., Walter, R. D. and Müller, S. (2000). Deletion of the parasite-specific insertions and mutation of the catalytic triad in glutathione reductase from chloroquine-sensitive Plasmodium falciparum 3D7. Molecular and Biochemical Parasitology 107, 169179.
Gromer, S., Arscott, L. D., Williams, C. H. Jr., Schirmer, R. H. and Becker, K. (1998). Human placenta thioredoxin reductase. Isolation of the selenoenzyme, steady state kinetics, and inhibition by therapeutic gold compounds. Journal of Biological Chemistry 273, 2009620101.
Gromer, S., Urig, S. and Becker, K. (2004). The thioredoxin system – from science to clinic. Medicinal Research Reviews 24, 4089.
Hirt, R. P., Müller, S., Embley, T. M. and Coombs, G. H. (2002). The diversity and evolution of thioredoxin reductase: new perspectives. Trends in Parasitology 18, 302308.
Holmgren, A. (1977). Bovine thioredoxin system. Purification of thioredoxin reductase from calf liver and thymus and studies of its function in disulfide reduction. Journal of Biological Chemistry 252, 46004606.
Kabe, Y., Ando, K., Hirao, S., Yoshida, M. and Handa, H. (2005). Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxidants & Redox Signaling 7, 395403.
Kanda, T., Engman, L., Cotgreave, I. A. and Powis, G. (1999). Novel water-soluble diorganyl tellurides with thiol peroxidase and antioxidant activity. Journal of Organic Chemistry 64, 81618169.
Krauth-Siegel, R. L. and Coombs, G. H. (1999). Enzymes of parasite thiol metabolism as drug targets. Parasitology Today 15, 404409.
Krnajski, Z., Gilberger, T. W., Walter, R. D., Cowman, A. F. and Müller, S. (2002). Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages. Journal of Biological Chemistry 277, 2597025975.
Leitsch, D., Kolarich, D., Wilson, I. B., Altmann, F. and Duchêne, M. (2007). Nitroimidazole action in Entamoeba histolytica: a central role for thioredoxin reductase. PLoS Biology 5, e211.
Luthman, M. and Holmgren, A. (1982). Rat liver thioredoxin and thioredoxin reductase: purification and characterization. Biochemistry 21, 66286633.
McMillan, P. J., Arscott, L. D., Ballou, D. P., Becker, K., Williams, C. H. Jr. and Müller, S. (2006). Identification of acid-base catalytic residues of high-Mr thioredoxin reductase from Plasmodium falciparum. Journal of Biological Chemistry 281, 3296732977.
McNaughton, M., Engman, L., Birmingham, A., Powis, G. and Cotgreave, I. A. (2004). Cyclodextrin-derived diorganyl tellurides as glutathione peroxidase mimics and inhibitors of thioredoxin reductase and cancer cell growth. Journal of Medicinal Chemistry 47, 233239.
Müller, S. (2004). Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Molecular Microbiology 53, 12911305.
Nakamoto, H. and Bardwell, J. C. (2004). Catalysis of disulfide bond formation and isomerization in the Escherichia coli periplasm. Biochimica et Biophysica Acta 1694, 111119.
Nogueira, C. W., Zeni, G. and Rocha, J. B. T. (2004). Organoselenium and organotellurium compounds: toxicology and pharmacology. Chemical Reviews 104, 62556285.
Powis, G. and Montfort, W. R. (2001). Properties and biological activities of thioredoxins. Annual Review in Pharmacology and Toxicology 41, 261295.
Smith, A. D., Guidry, C. A., Morris, V. C. and Levander, O. A. (1999). Aurothioglucose inhibits murine thioredoxin reductase activity in vivo. Journal of Nutrition 129, 194198.
Stangherlin, E. C., Favero, A. M., Zeni, G., Rocha, J. B. and Nogueira, C. W. (2005). Teratogenic vulnerability of Wistar rats to diphenyl ditelluride. Toxicology 207, 231239.
Trager, W. and Jensen, J. B. (1976). Human malaria parasites in continuous culture. Science 193, 673675.
Urig, S. and Becker, K. (2006). On the potential of thioredoxin reductase inhibitors for cancer therapy. Seminars in Cancer Biology 16, 452465.
World Health Organization (2001). Global Prevalence and Incidence of Selected Curable Sexually Transmitted Infections. World Health Organization, Geneva.
Williams, C. H., Arscott, L. D., Müller, S., Lennon, B. W., Ludwig, M. L., Wang, P. F., Veine, D., Becker, K. and Schirmer, R. H. (2000). Thioredoxin reductase two modes of catalysis have evolved. European Journal of Biochemistry 267, 61106117.


Differential inhibition of high and low Mr thioredoxin reductases of parasites by organotelluriums supports the concept that low Mr thioredoxin reductases are good drug targets

  • P. J. McMILLAN (a1), E. M. PATZEWITZ (a1), S. E. YOUNG (a1), G. D. WESTROP (a2), G. H. COOMBS (a2), L. ENGMAN (a3) and S. MÜLLER (a1)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed