Advertisement

Polyamine and Glutathione Biosynthetic Enzymes from Trypanosoma Brucei and Trypanosoma Cruzi

  • Lisa N. Kinch
  • Deirdre L. Brekken
  • Margaret A. Phillips
Chapter

Abstract

The polyamines putrescine and spermidine are ubiquitous cell growth factors that are synthesized from ornithine and S-adenosylmethionine (Fig. 1). Inhibition of the polyamine biosynthetic enzymes, or the knockout of genes encoding these enzymes, causes cell growth arrest in both prokaryotic and eukaryotic cells, e.g. E. coli; (Tabor and Tabor, 1984), mammalian cells (Svensson and Persson, 1996), yeast (Cohn et al., 1980), and Trypanosoma brucei (Li et al., 1996). A number of inhibitors of polyamine biosynthesis have been demonstrated to be effective anti-trypanosomal agents (Wang, 1995), identifying these enzymes as drug targets for the treatment of trypanosomatid infections. In addition to the common pathway found in almost all cell types, protozoa from the family Trypanosomatidae synthesize a unique cofactor that is a conjugate of spermidine and glutathione (Fig. 1). This cofactor, trypanothione, is required to maintain redox balance in the cell (Fairlamb and Le Quesne, 1997).

Keywords

Ornithine Decarboxylase Trypanosoma Cruzi Trypanosoma Brucei Buthionine Sulfoximine Subunit Interface 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Almrud, J.J., Oliveira, M.A., Grishin, N.V., Phillips, M.A. and Hackert, M.L. (1999). Crystal structure of human ornithine decarboxylase at 2.1 A resolution: structural perspectives of antizyme binding. submitted.Google Scholar
  2. Arrick, B.A., Griffith, O.W. and Cerami, A. (1981). Inhibition of glutathione synthesis as a chemotherapeutic strategy for trypanosomiasis. J. Exp. Med. 153, 720–725.PubMedCrossRefGoogle Scholar
  3. Atamna, H. and Ginsburg, H. (1997). The malaria parasite supplies glutathione to its host cell: Investigation of glutatione transport and metabolism in human erythrocytes infected with P. falciparum. Eur. J. Biochem. 250, 670–679.PubMedCrossRefGoogle Scholar
  4. Bacchi, C.J., Garofalo, J. Ciminelli, M. Rattendi, D., Goldberg, B., McCann, P.P. and Yarlett, N. (1993). Resistance to DL-a-difluoromethylornithine by clinical isolates of Trypanosoma brucei rhodesiense. Role of S-adenosylmethionine. Biochemical Pharmacol. 46, 471–481.CrossRefGoogle Scholar
  5. Bacchi, CJ, Nathan, H.C., Yarlett, N., Goldberg, B., McCann, P.P., Bitonti, A.J. and Sjoerdsma, A. (1992). Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor. Antimicrobial agents and Chemotherapy. 36, 2736–40.PubMedCrossRefGoogle Scholar
  6. Bacchi, C.J. and Yarlett, N. (1993). Effects of antagonists of polyamine metabolism of African trypanosomes. Acta Tropica. 54, 225–236.PubMedCrossRefGoogle Scholar
  7. Blundell, TL (1996) Structure-based drug design. Nature, 384 supp., 23–26.Google Scholar
  8. Bitonti, A.J., Bacchi, C.J., McCann, P.P. and Sjoerdsma, A. (1985). Catalytic irreversible inhibition of Trypanosoma brucei brucei ornithine decarboxylase by substrate and product analogs and their effects on murine trypanosomiasis. Biochemical Pharmacology. 34, 1773–1777.PubMedCrossRefGoogle Scholar
  9. Brekken, D.L. and Phillips, M.A. (1998). Trypanosoma brucei y-glutamylcysteine synthetase: characterization of the kinetic mechanism and the role of Cys-319 in cystamine inactivation. J. Biol. Chem. 273, 26317–26322.PubMedCrossRefGoogle Scholar
  10. Brooks, H.B. and Phillips, M.A. (1997). Characterization of the reaction mechanism of Trypanosoma brucei ornithine decarboxylase by multiwavelength stopped-flow spectroscopy. Biochemistry. 36, 15147–15155.PubMedCrossRefGoogle Scholar
  11. Cohn, M.S., Tabor, C.W. and Tabor, H. (1980). Regulatory mutations affecting ornithine decarboxylase activity in Saccharomyces cerevisiae. J. Bacterol. 142, 791–799.Google Scholar
  12. Coleman, C.S., Stanley, B.A., Viswanath, R. and Pegg, A.E. (1994). Rapid exchange of subunits of mammalian ornithine decarboxylase. J Biol Chem. 269, 3155–3158.PubMedGoogle Scholar
  13. Copeland, R.A. (1996). Enzymes: a practical introduction to structure, mechanism, and data analysis. New York, Wiley-VCH.Google Scholar
  14. Das, B., Gupta, R. and Madhubala, R. (1997). Combined action of inhibitors of Sadenosylmethionine decarboxylase with an antimalarial drug, chloroquine, on Plasmodium falciparum. J. Euk. Microbiol. 44, 12–17.PubMedCrossRefGoogle Scholar
  15. Dubois, V.L., Platel, D.F.N., Pauly, G. and Tribouley-Duret, J. (1995). Plasmodium berghei: Implication of intracellular glutathione and its related enzyme in chloroquine resistance in vivo. Exp. Parasitol. 81, 117–124.PubMedCrossRefGoogle Scholar
  16. Dumas, C., 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.PubMedCrossRefGoogle Scholar
  17. Ekstrom, J.L., Mathews, I.I., Stanley, B.A., Pegg, A.E. and Ealick, S.E. (1999). The crystal structure of human S-adenosylmethionine decarboxylase at 2.25 A resolution reveals a novel fold. Structure. 7, 583–595.PubMedCrossRefGoogle Scholar
  18. Fairlamb, A.H. and Le Quesne, S.A. (1997). Polyamine metabolism in Trypanosomes. Trypanosomiasis and Leishmaniasis. G. Hide, J. Mottram, G. Coombs and P. Homlmes, CAB International: 149–161.Google Scholar
  19. Geary, T.G., Divo, A.A., Bonanni, L.C. and Jensen, J.B. (1985). Nutritional requirements of Plasmodium falciparum in culture. III. Further observations on essential nutrients and antimetabolites. J. Protozool. 32, 608–613.PubMedGoogle Scholar
  20. Goldberg, B., Rattendi, D., Lloyd, D., Yarlett, N. and Bacchi, C.J. (1999). Kinetics of Sadenosylmethionine cellular transport and protein methylation in Trypanosma brucei brucei and Trypanosoma brucei rhodesiense. Archives of Biochemistry and Biophysics. 364, 13–18.PubMedCrossRefGoogle Scholar
  21. Griffith, O.W. and Mulcahy, R.T. (1999). The enzymes of glutathione synthesis: gglutamylcysteine synthetase. Advances in Enzymology and Related Areas of Molecular Biology. D. Purich. New York, John Wiley zhaohuan Sons, Inc. 73: 209–267.Google Scholar
  22. Grishin, N.V., Osterman, A.L., Brooks, H.B., Phillips, M.A. and Goldsmith, E.J. (1999). The X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with a-difluoromethylornithine. Biochemistry, in press.Google Scholar
  23. Grishin, NV, Osterman, A.L., Goldsmith, E.J. and Phillips, M.A. (1996). Crystallization and preliminary x-ray studies of ornithine decarboxylase from Trypanosoma brucei. Proteins. 24, 272–273.PubMedCrossRefGoogle Scholar
  24. Grishin, NV, Phillips, M.A. and Goldsmith, E.J. (1995). Modeling of the spatial structure of eukaryotic ornithine decarboxylases. Protein Science. 4, 1291–1304.PubMedCrossRefGoogle Scholar
  25. Grondin, K., Haimeur, A., Mukhopadhyay, R., Rosen, B.P. and Ouellette, M. (1997). Co-amplification of the y-glutamylcysteine synthetase gene gshl and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J. 16, 3057–3065.PubMedCrossRefGoogle Scholar
  26. Hiromi, K. (1979). Kinetics of Fast Reactions. New York, Halsted Press.Google Scholar
  27. Hunter, W.N. (1997). A structure-based approach to drug discovery; crystallography and implications for the development of antiparasite drugs. Parasitology. 114, S17 - S29.PubMedGoogle Scholar
  28. Hussein, A.S. and Walter, R.D. (1995). Purification and charactization of g-glutamylcysteine synthetase from Ascaris suum. Mol. and Biochem. Parasitol. 72, 57–64.Google Scholar
  29. Iten, M., Mett, H., Evans, A., Enyaru, J.C.K., Brun, R. and Kaminsky, R. (1997). Alternations in ornithine decarboxylase characteristics account for tolerance of Trypanosoma brucei rhodeisiense to D,L-a-difluoromethylornithine. Antimicrobial agents and chemotherapy. 41, 1922–1925.PubMedGoogle Scholar
  30. Kern, A.D., Oliveira, M.A., Coffino, P. and Hackert, M. (1999). Structure of mammalian ornithine decarboxylase at 1.6 A resolution: Stereochemical implications of PLPdependent amino acid decarboxylase. Structure. 7, 567–581.PubMedCrossRefGoogle Scholar
  31. Kinch, L.N., Scott, J., Ullman, B. and Phillips, M.A. (1999). S-adenosylmethionine from Trypanosoma cruzi: cloning, expression and kinetic characterization of the recombinant enzyme. Mol Biochem Parasitol. 101, 1–11.PubMedCrossRefGoogle Scholar
  32. Kunkel, T.A. (1985). Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc. Natl. Acad. Sci. U.S.A. 82, 488.PubMedCrossRefGoogle Scholar
  33. Kuzoe, F.A.S. (1993). Current situation of African trypanosomiasis. Acta Trop. 54, 153–162.PubMedCrossRefGoogle Scholar
  34. Li, F., Hua, S.B., Wang, C.C. and Gottesdiener, K.M. (1996). Procyclic Trypanosoma brucei cell lines deficient in ornithine decarboxylase activity. Mol. Biochem. Parasitol. 78, 227–236.PubMedCrossRefGoogle Scholar
  35. Lueder, D.V. and Phillips, M.A. (1996). Characterization of Trypanosoma brucei yglutamylcysteine synthetase, an essential enzyme in the biosynthesis of trypanothione. J. Biol. Chem. 271, 17485–17490.PubMedCrossRefGoogle Scholar
  36. Markham, G.D., Tabor, C.W. and Tabor, H. (1983). S-adenosylmethionine decarboxylase (Escherichia Coli). In: Tabor H, Tabor CW, eds. Methods in Enzymology. 94th ed. Academic Press,. 228–230.Google Scholar
  37. Mehlotra, R.K. (1996). Antioxidant defense mechanisms in parasitic protozoa. Clinical Reviews in Microbiology. 22, 295–314.CrossRefGoogle Scholar
  38. Meshnick, S.R., Chang, K.P. and Cerami, A. (1977). Biochem. Pharmacol. 26, 1923–1928.PubMedCrossRefGoogle Scholar
  39. Moncada, C., Repetto, Y. and Aldunate, J., Letelier, M.E. and Morello, A. (1989). Role of glutathione in the suseptibility of Trypanosoma cruzi to drugs. Comparative Biochemistry and Physiology-C: Comparative Pharmacology and Toxicology. 94, 87–91Google Scholar
  40. Osterman, A.L., Brooks, H.B., Jackson, L., Abbott, J.J. and Phillips, M.A. (1999). Lys-69 plays a key role in catalysis by T. brucei ornithine decarboxylase through acceleration of the substrate binding, decarboxylation and product release steps. Biochemistry. in press Google Scholar
  41. Osterman, A.L., Brooks, H.B., Riso, J.. and Phillips, M.A. (1997). The role of Arg-277 in the binding of pyridoxal 5’-phosphate to Trypanosoma brucei ornithine decarboxlyase. Biochemistry. 36, 4558–4567.PubMedCrossRefGoogle Scholar
  42. Osterman, A.L., Grishin, N.V., Kinch, L.N. and Phillips, M.A. (1994). Formation of functional cross-species heterodimers of ornithine decarboxylase. Biochemistry. 33, 13662–13667.PubMedCrossRefGoogle Scholar
  43. Osterman, A.L., Kinch, L.N., Grishin, N.V. and Phillips, M.A. (1995). Acidic residues important for substrate binding and cofactor reactivity in eukaryotic ornithine decarboxylase identified by alanine scanning mutagenesis. J. Biol. Chem. 270, 11797–11802.PubMedCrossRefGoogle Scholar
  44. Osterman, A.L., Lueder, D.V., Quick, M., Myers, D., Canagarajah, B.J. and Phillips, M.A. (1995). Domain organization and a protease-sensitive loop in eukaryotic ornithine decarboxylase. Biochemistry. 34, 13431–13436.PubMedCrossRefGoogle Scholar
  45. Pegg, A.E., Xiong, H., Feith, D.J. and Shantz, L.M. (1998). S-adenosylmethionine decarboxylase: structure, function and regulation by polyamines. Biochem Soc Trans. 26, 580–586.PubMedGoogle Scholar
  46. Phillips, M.A. (1999). Ornithine decaboxylase. in The encyclopedia of molecular biology. T. Creighton. New York, John Wiley zhaohuan Sons.Google Scholar
  47. Poso, H., Hannonen, P., Himberg, J. and Janne, J. (1976). Adenosylmethionine decarboxylase from various organisms: relation of the putrescine activation of the enzyme to the ability of the organism to synthesize spermine. Biochem Biophys Res Commun 68, 227–234.PubMedCrossRefGoogle Scholar
  48. Poulin, R., Lu, L., Ackermann, B., Bey, P. and Pegg, A.E. (1992). Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by adifluoromethylornithine: characterization of sequences at the inhibitor and coenzyme binding sites. J Biol Chem. 267, 150–158.PubMedGoogle Scholar
  49. Schirmer, R.H., Muller, J.G. and Krauth-Siegel, R.L. (1995). Disulfide-reductase inhibitors as chemotherapeutic agents: the design of drugs for trypanosomiasis and malaria. Angew. Chem. Int. Ed. Engl. 34, 141.Google Scholar
  50. Schroder, C.P., Godwin, A.K., O’Dwyer, P.J., Tew, K.D., Hamilton, T.C. and Ozols, R.F. (1996). Glutathione and drug resistance. Cancer Investigation. 14, 158–168.PubMedCrossRefGoogle Scholar
  51. Segel, I.H. (1975). Enzyme kinetics, behavior and analysis of rapid equilibrium and steadystate enzyme systems. New York, John Wiley zhaohuan Sons, Inc.Google Scholar
  52. Stanley, B.A. and Shantz, L.M. (1994). S-adenosylmethionine decarboxylase structure-function relationships. Biochem Soc Trans. 22, 863–869.PubMedGoogle Scholar
  53. Svensson, F. and Persson, L. (1996). Regulation of ornithine decarboxlyase and Sadenosylmethionine decarboxlyase in a polyamine auxotrophic cell line. Mol. and Cell. Biochem. 162, 113–119.Google Scholar
  54. Tabor, C.W. and Tabor, H. (1984). Polyamines. Ann Rev Biochem. 53, 749–790.CrossRefGoogle Scholar
  55. Tobias, K.E. and Kahana, C. (1993). Intersubunit location of the active site of mammalian ornithine decarboxylase as determined by hybridization of site-directed mutants. Biochemistry. 32, 5842–5847.PubMedCrossRefGoogle Scholar
  56. Wang, C.C. (1995). Molecular mechanisms and therapeutic approaches to the treatment of African Trypanosomiasis. Annu. Rev. Pharmacol. Toxicol. 35, 93–127.PubMedCrossRefGoogle Scholar
  57. Xiong, H., Stanley, B.A. and Pegg, A.E. (1999). Role of Cysteine-82 in the catalytic mechanism of human S-adenosylmethionine decarboxylase. Biochemistry. 38, 2462–2470.PubMedCrossRefGoogle Scholar
  58. Yakubu, M.A., Majumder, S. and Kierszenbaum, F. (1993). Inhibition of S-adenosyl-Lmethionine (adomet) decarboxylase by the decarboxylated adomet analog 5‘{[(Z)-4amino-2-butenyl]methylamino} -5’-deoxyadenosine (MDL73811) decreases the capacities of Trypanosoma cruzi to infect and multiply within a mammalian host cell. J. Parasitol. 79, 525–532.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Lisa N. Kinch
    • 1
  • Deirdre L. Brekken
    • 1
  • Margaret A. Phillips
    • 1
  1. 1.University of Texas Southwestern Medical SchoolDallasUSA

Personalised recommendations