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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

Published online by Cambridge University Press:  04 November 2008

P. J. McMILLAN ,
E. M. PATZEWITZ ,
S. E. YOUNG ,
G. D. WESTROP ,
G. H. COOMBS ,
L. ENGMAN  and
S. MÜLLER
P. J. McMILLAN
Affiliation:
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
E. M. PATZEWITZ
Affiliation:
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
S. E. YOUNG
Affiliation:
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
G. D. WESTROP
Affiliation:
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, UK
G. H. COOMBS
Affiliation:
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, UK
L. ENGMAN
Affiliation:
Department of Biochemistry and Organic Chemistry, University of Uppsala, Box 576, SE-751 23 Uppsala, Sweden
S. MÜLLER*
Affiliation:
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
*
*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: [email protected]
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Summary

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.

Keywords

inhibitionthioredoxin systemmalariaorganotellurium compoundsTrichomonasPlasmodium
Type
Research Article
Information
Parasitology , Volume 136 , Issue 1 , January 2009 , pp. 27 - 33
Copyright
Copyright © 2008 Cambridge University Press

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References

REFERENCES

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, 2283–2292.CrossRefGoogle ScholarPubMed
Arner, E. S. and Holmgren, A. (2006). The thioredoxin system in cancer. Seminars in Cancer Biology 16, 420–426.CrossRefGoogle ScholarPubMed
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, 1449–1462.CrossRefGoogle ScholarPubMed
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, 6118–6125.CrossRefGoogle ScholarPubMed
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, 453–462.CrossRefGoogle ScholarPubMed
Carlton, J. M., Hirt, R. P., Silva, J. C. et al. (2007). Draft genome sequence of the sexually transmitted pathogen Trichomonas vaginalis. Science 315, 207–212.CrossRefGoogle ScholarPubMed
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, 5249–5256.CrossRefGoogle ScholarPubMed
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, 539–544.CrossRefGoogle ScholarPubMed
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, 5091–5100.CrossRefGoogle ScholarPubMed
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, 153–161.CrossRefGoogle ScholarPubMed
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, 323–330.Google ScholarPubMed
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, 1140–1147.CrossRefGoogle ScholarPubMed
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, 169–179.CrossRefGoogle ScholarPubMed
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, 20096–20101.CrossRefGoogle ScholarPubMed
Gromer, S., Urig, S. and Becker, K. (2004). The thioredoxin system – from science to clinic. Medicinal Research Reviews 24, 40–89.CrossRefGoogle ScholarPubMed
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, 302–308.CrossRefGoogle ScholarPubMed
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, 4600–4606.CrossRefGoogle ScholarPubMed
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, 395–403.CrossRefGoogle ScholarPubMed
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, 8161–8169.CrossRefGoogle ScholarPubMed
Krauth-Siegel, R. L. and Coombs, G. H. (1999). Enzymes of parasite thiol metabolism as drug targets. Parasitology Today 15, 404–409.CrossRefGoogle ScholarPubMed
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, 25970–25975.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Luthman, M. and Holmgren, A. (1982). Rat liver thioredoxin and thioredoxin reductase: purification and characterization. Biochemistry 21, 6628–6633.CrossRefGoogle ScholarPubMed
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, 32967–32977.CrossRefGoogle ScholarPubMed
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, 233–239.CrossRefGoogle ScholarPubMed
Müller, S. (2004). Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Molecular Microbiology 53, 1291–1305.CrossRefGoogle ScholarPubMed
Nakamoto, H. and Bardwell, J. C. (2004). Catalysis of disulfide bond formation and isomerization in the Escherichia coli periplasm. Biochimica et Biophysica Acta 1694, 111–119.CrossRefGoogle ScholarPubMed
Nogueira, C. W., Zeni, G. and Rocha, J. B. T. (2004). Organoselenium and organotellurium compounds: toxicology and pharmacology. Chemical Reviews 104, 6255–6285.CrossRefGoogle ScholarPubMed
Powis, G. and Montfort, W. R. (2001). Properties and biological activities of thioredoxins. Annual Review in Pharmacology and Toxicology 41, 261–295.CrossRefGoogle ScholarPubMed
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, 194–198.CrossRefGoogle ScholarPubMed
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, 231–239.CrossRefGoogle ScholarPubMed
Trager, W. and Jensen, J. B. (1976). Human malaria parasites in continuous culture. Science 193, 673–675.CrossRefGoogle ScholarPubMed
Urig, S. and Becker, K. (2006). On the potential of thioredoxin reductase inhibitors for cancer therapy. Seminars in Cancer Biology 16, 452–465.CrossRefGoogle ScholarPubMed
World Health Organization (2001). Global Prevalence and Incidence of Selected Curable Sexually Transmitted Infections. World Health Organization, Geneva.Google Scholar
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, 6110–6117.CrossRefGoogle ScholarPubMed