Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress

Molecular Microbiology

Volumn 35, Issue 3, 2000, Pages 542-552

  Krieger, S ^a   Schwarz, W ^a   Arlyanayagam, M R ^b   Fairlamb, A H ^b   Krauth Siegel, R L ^c   Clayton, C ^a  

^a UNIVERSITY OF HEIDELBERG   (Germany)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

^c Biochemie Zentrum der Univ H   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

MELARSENOXIDE; THIOL; TRYPANOTHIONE; TRYPANOTHIONE REDUCTASE;

ANIMAL EXPERIMENT; ARTICLE; EXPERIMENTAL INFECTION; GENE; MOUSE; NONHUMAN; OXIDATIVE STRESS; PARASITE VIRULENCE; PRIORITY JOURNAL; PROMOTER REGION; TRYPANOSOMA BRUCEI; TRYPANOSOMIASIS;

ANIMALS; ANTI-BACTERIAL AGENTS; ANTIPROTOZOAL AGENTS; ARSENICALS; CELL CYCLE; CELL DIVISION; DOXYCYCLINE; ENZYME INHIBITORS; MICE; MICE, INBRED BALB C; MUTATION; NADH, NADPH OXIDOREDUCTASES; OXIDATIVE STRESS; PROMOTER REGIONS (GENETICS); SULFHYDRYL COMPOUNDS; TETRACYCLINE; TRYPANOSOMA BRUCEI BRUCEI; TRYPANOSOMIASIS, AFRICAN; VIRULENCE;

ANIMALIA; KINETOPLASTIDA; PROTOZOA; TRYPANOSOMA; TRYPANOSOMA BRUCEI;

EID: 0033977079     PISSN: 0950382X     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1365-2958.2000.01721.x     Document Type: Article

References (44)

1. Beverley, S.M., and Clayton, C.E. (1993) Transfection of Leishmania and Trypanosoma brucei by electroporation. Methods Mol Biol 21: 333-348.
2. Biebinger, S., Wirtz, L.E., and Clayton, C.E. (1997) Vectors for inducible over-expression of potentially toxic gene products in bloodstream and procyclic Trypanosoma brucei. Mol Biochem Parasitol 85: 99-112.
3. Bogdan, C., and Röllinghoff, M. (1999) How do protozoan parasites survive inside macrophages? Parasitol Today 15: 22-28.
4. Borges, A., Cunningham, M.L., Tovar, J., and Fairlamb, A.H. (1995) Site-directed mutagenesis of the redox-active cysteines of Trypanosoma cruzi trypanothione reductase. Eur J Biochem 228: 745-752.
5. Carter, N.S., and Fairlamb, A.H. (1993) Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature 361: 173-176.
6. Clayton, C.E. (1999) Genetic manipulation of Kinetoplastida. Parasitol Today 15: 372-378.
7. Cunningham, M.L., Zvelebil, M.J., and Fairlamb, A.H. (1994) Mechanism of inhibition of trypanothione reductase by trivalent organic arsenicals. Eur J Biochem 221: 285-295.
8. Dumas, C., Oellette, M., Tovar, J., Cunningham, M.L., Fairlamb, A., Tamar, S., et al. (1997) Disruption of the trypanothione reductase gene of Leishmania decreases its ability to survive oxidative stress in macrophages. EMBO J 16: 2590-2598.
9. Duszenko, M., Mühlstädt, K., and Broder, A. (1992) Cysteine is an essential growth factor for Trypanosoma brucei bloodstream forms. Mol Biochem Parasitol 50: 269-274.
10. Ellman, G.L. (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82: 70-72.
11. Fairlamb, A.H., and Cerami, A. (1985) Identification of a novel, thiol-containing co-factor essential for glutathione reductase enzyme activity in trypanosomatids. Mol Biochem Parasitol 14: 187-198.
12. Fairlamb, A.H., and Cerami, A. (1992) Metabolism and functions of trypanothione in the Kinetoplastida. Annu Rev Microbiol 46: 695-729.
13. Fairlamb, A.H., Blackburn, P., Ulrich, P., Chait, B.T., and Cerami, A. (1985) Trypanothione: a novel bis(glutathionyl) spermidine cofactor for glutathione reductase in trypanosomatids. Science 227: 1485-1487.
14. Fairlamb, A.H., Henderson, G.B., and Cerami, A. (1989) Trypanothione is the primary target for arsenical drugs against African trypanosomiasis. Proc Natl Acad Sci USA 86: 2607-2611.
15. Gommel, D.U., Nogoceke, E., Morr, M., Kiess, M., Kalisz, H.M., and Flohé, L. (1997) Catalytic characteristics of tryparedoxin. Eur J Biochem 248: 913-918.
16. Grondin, K., Haimeur, A., Mukhopadhyay, R., Rosen, B.P., and Ouellette, M. (1997) Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J 16: 3057-3065.
17. Gueiros-Filho, F.J., and Beverley, S.M. (1996) Selection against the dihydrofolate reductase-thymidylate synthase (DHFR-TS) locus as a probe of genetic alterations in Leishmania major. Mol Cell Biol 16: 5655-5663.
18. Henderson, G.H., Fairlamb, A.H., and Cerami, A. (1987) Trypanothione dependent peroxide metabolism in Crithidia fasciculata and Trypanosoma brucei. Mol Biochem Parasitol 24: 39-45.
19. Hunter, W.N., Bailey, S., Habash, J., Harrop, S.J., Helliwell, J.R., Aboagye Kwarteng, T., et al. (1992) Active site of trypanothione reductase. A target for rational drug design. J Mol Biol 227: 322-333.
20. Kelly, J.M., Taylor, M.C., Smith, K., Hunter, K.J., and Fairlamb, A.H. (1993) Phenotype of recombinant Leishmania donovani and Trypanosoma cruzi which over-express trypanothione reductase: sensitivity towards agents that are thought to induce oxidative stress. Eur J Biochem 218: 29-37.
21. Kistner, A., Gossen, M., Zimmermann, F., Jerecic, J., Ullmer, C., Lubbert, H., and Bujard, H. (1996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci USA 93: 10933-10938.
22. Krauth-Siegel, R.L., and Schöneck, R. (1995) Flavoprotein structure and mechanism. 5. Trypanothione reductase and lipoamide dehydrogenase as targets for a structure-based drug design. FASEB J 9: 1138-1146.
23. Krauth-Siegel, R.L., Enders, B., Henderson, G.B., Fairlamb, A.H., and Schirmer, R.H. (1987) Trypanothione reductase from Trypanosoma cruzi. Purification and characterization of the crystalline enzyme. Eur J Biochem 164: 123-128.
24. Krauth-Siegel, R.L., Jacoby, E.M., and Schirmer, R.H. (1995) Trypanothione and N1-glutathionylspermidine: isolation and determination. Methods Enzymol 251: 287-294.
25. Krieger, S. (1998) Die Trypanothion-Reduktase in Trypanosoma brucei: Etablierung und Charakterisierung einer TR-defizienten Zellinie. PhD Thesis, Universität Heidelberg.
26. Lee, J., Dawes, I.W., and Roe, J.H. (1997) Isolation, expression, and regulation of the pgr1 (+) gene encoding glutathione reductase absolutely required for the growth of Schizosaccharomyces pombe. J Biol Chem 272: 23042-23049.
27. Légaré, D., Papadopoulou, B., Roy, G., Mukhopadhyay, R., Haimeur, A., Dey, S., et al. (1997) Efflux systems and trypanothione levels in arsenite-resistant Leishmania. Exp Parasitol 87: 275-282.
28. Lorenz, P., Meier, A., Erdmann, R., Baumgart, E., and Clayton, C. (1998) Elongation and clustering of glycosomes in Trypanosoma brucei overexpressing the glycosomal Pex11p. EMBO J 17: 3542-3555.
29. Lüdemann, H., Dormeyer, M., Sticherling, C., Stallmann, D., Follmann, H., and Krauth-Siegel, R.L. (1998) Trypanosoma brucei tryparedoxin, a thioredoxin-like protein in African trypanosomes. FEBS Left 431: 381-385.
30. Matthews, K.R., and Gull, K. (1997) Commitment to differentiation and cell cycle re-entry are coincident but separate events in the transformation of African trypanosomes from their bloodstream to their insect form. J Cell Sci 110: 2609-2618.
31. Mortenson, R.M., Conner, D.A., Chao, S., Geisterfer-Lowrance, A.A., and Seidman, J.G. (1992) Production of homozygous mutant ES cells with a single targeting construct. Mol Cell Biol 12: 2391-2395.
32. Muller, E.G. (1996) A glutathione reductase mutant of yeast accumulates high levels of oxidized glutathione and requires thioredoxin for growth. Mol Biol Cell 7: 1805-1813.
33. Nogoceke, E., Gommel, D.U., Kiess, M., Kalisz, H.M., and Flöhé, L. (1997) A unique cascade of oxidoreductases catalyses trypanothione-mediated peroxide metabolism in Crithidia fasciculata. Biol Chem 378: 827-836.
34. Penninckx, M.J., and Elskens, M.T. (1993) Metabolism and functions of glutathione in micro-organisms. Adv Microb Physiol 34: 239-301.
35. Robinson, D.R., Sherwin, T., Ploubidou, A., Byard, E.H., and Gull, K. (1995) Microtubule polarity and dynamics in the control of organelle positioning, segregation and cytokinesis in the trypanosome cell cycle. J Cell Biol 128: 1163-1172.
36. Schirmer, R.H., Krauth-Siegel, R.L., and Schulz, G.E. (1989) Glutathione reductase. In Glutathione: Chemical, Biochemical and Medical Aspects - Part A. Dolphin, D., Poulson, R., and Avramovic, O. (eds). New York: John Wiley and Sons, pp. 553-595.
37. Shames, S.L., Fairlamb, A.H., Cerami, A., and Walsh, C.T. (1986) Purification and characterization of trypanothione reductase from Crithidia fasciculata, a newly discovered member of the family of disulfide-containing flavoprotein reductases. Biochemistry 25: 3519-3526.
38. Shim, H., and Fairlamb, A.H. (1988) Levels of polyamines, glutathione and glutathione-spermidine conjugates during growth of the insect trypanosomatid Crithidia fasciculata. J Gen Microbiol 134: 807-817.
39. Tovar, J., and Fairlamb, A.H. (1996) Extrachromosomal, homologous expression of trypanothione reductase and its complementary mRNA in Trypanosoma cruzi. Nucleic Acids Res 24: 2942-2949.
40. Tovar, J., Wilkinson, S., Mottram, J.C., and Fairlamb, A.H. (1998a) Evidence that trypanothione reductase is an essential enzyme in Leishmania by targeted replacement of the tryA gene locus. Mol Microbiol 29: 653-660.
41. Tovar, J., Cunningham, M.L., Smith, A.C., Croft, S.L., and Fairlamb, A.H. (1998b) Down-regulation of Leishmania donovani trypanothione reductase by heterologous expression of a trans-dominant mutant homologue: effect on parasite intracellular survival. Proc Natl Acad Sci USA 95: 5311-5316.
42. Wirtz, E., and Clayton, C. (1995) Inducible gene expression in trypanosomes mediated by a prokaryotic repressor. Science 268: 1179-1183.
43. Yarlett, N., Goldberg, B., Nathan, H.C., Garofalo, J., and Bacchi, C.J. (1991) Differential sensitivity of Trypanosoma brucei rhodesiense isolates to in vitro lysis by arsenicals. Exp Parasitol 72: 205-215.
44. Zhang, Y., König, I., and Schirmer, R.H. (1988) Glutathione reductase-deficient erythrocytes as host cells of malarial parasites. Biochem Pharmacol 37: 861-865.