Antiparasitic Chemotherapy:

Tinkering with the Purine Salvage Pathway
  • Alok Kumar Datta
  • Rupak Datta
  • Banibrata Sen
Chapter
Part of the Advances In Experimental Medicine And Biology book series (AEMB, volume 625)

Abstract

Distinguishable differences between infecting organisms and their respective hosts with respect to metabolism and macromolecular structure provide scopes for detailed characterization of target proteins and/or macromolecules as the focus for the devel opment of selective inhibitors. In order to develop a rational approach to antiparasitic chemo therapy, finding differences in the biochemical pathways of the parasite with respect to the host it infects is therefore of primary importance. Like most parasitic protozoan, the genus Leishmania is an obligate auxotroph of purines and hence for requirement of purine bases depends on its own purine salvage pathways.

Keywords

Visceral Leishmaniasis Toxoplasma Gondii Purine Base Leishmania Species Adenosine Kinase 
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.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Chang KP, Fong D, Bray RS, eds. Biology of Leishmania and leishmaniasis in “Leishmaniasis”. Volume 1. Amsterdam: Elsevier Science Publishers BV, 1985:1–30.Google Scholar
  2. 2.
    Barrett MP, Mottram JC, Coombs GH. Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. Trends Microbiol 1999; 7(2):82–88.PubMedCrossRefGoogle Scholar
  3. 3.
    Killick-Kendrick R, Molyneux DH, Hommel M et al. Leishmania in phlebotomid sandflies. V. The nature and significance of infections of the pylorus and ileum of the sandfly by leishmaniae of the braziliensis complex. Proc R Soc Lond B Biol Sci 1977; 198(1131):191–199.PubMedCrossRefGoogle Scholar
  4. 4.
    Chang KP. Leishmania donovani: Promastigote—macrophage surface interactions in vitro. Exp Parasitol 1979; 48(2):175–189.PubMedCrossRefGoogle Scholar
  5. 5.
    el Kouni MH. Potential chemotherapeutic targets in the purine metabolism of parasites. Pharmacol Ther 2003; 99(3):283–309.PubMedCrossRefGoogle Scholar
  6. 6.
    Pratt DM, David JR. Monoclonal antibodies recognizing determinants specific for the promastigote state of Leishmania mexicana. Mol Biochem Parasitol 1982; 6(5):317–327.PubMedCrossRefGoogle Scholar
  7. 7.
    Jaffe CL, Bennett E, Grimaldi Jr G et al. Production and characterization of species-specific monoclonal antibodies against Leishmania donovani for immunodiagnosis. J Immunol 1984; 133(1):440–447.PubMedGoogle Scholar
  8. 8.
    Looker DL, Berens RL, Marr JJ. Purine metabolism in Leishmania donovani amastigotes and promastigotes. Mol Biochem Parasitol 1983; 9(1):15–28.PubMedCrossRefGoogle Scholar
  9. 9.
    Dwyer DM, Langreth SG, Dwyer NK. Evidence for a polysaccharide surface coat in the developmental stages of Leishmania donovani: A fine structure-cytochemical study. Z Parasitenkd 1974; 43(4):227–249.PubMedCrossRefGoogle Scholar
  10. 10.
    Janovy Jr J. Respiratory changes accompanying Leishmania to leptomonad transformation in Leishmania donovani. Exp Parasitol 1967; 20(1):51–55.PubMedCrossRefGoogle Scholar
  11. 11.
    Krassner SM, Morrow CD, Flory B. Inhibition of Leishmania donovani amastigote-to-promastigote transformation by infected hamster spleen lymphocyte lysates. J Protozool 1980; 27(l):87–92.PubMedGoogle Scholar
  12. 12.
    Konigk E, Putfarken B. Stage-specific differences of a perhaps signal-transferring system in Leishmania donovani. Tropenmed Parasitol 1980; 31(4):421–424.PubMedGoogle Scholar
  13. 13.
    Peterson DS, Milhous WK, Wellems TE. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci USA 1990; 87(8):3018–3022.PubMedCrossRefGoogle Scholar
  14. 14.
    Ring CS, Sun E, McKerrow JH et al. Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci USA 1993; 90(8):3583–3587.PubMedCrossRefGoogle Scholar
  15. 15.
    Foote SJ, Galatis D, Cowman AF. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc Natl Acad Sci USA 1990; 87(8):3014–3017.PubMedCrossRefGoogle Scholar
  16. 16.
    Trager W. Recent progress in some aspects of the physiology of parasitic protozoa. J Parasitol 1970; 56(4):627–633.PubMedCrossRefGoogle Scholar
  17. 17.
    Walsh CJ, Sherman IW. Purine and pyrimidine synthesis by the avian malaria parasite, Plasmodium lophurae. J Protozool 1968; 15(4):763–770.PubMedGoogle Scholar
  18. 18.
    Bone GJ, Steinert M. Isotopes incorporated in the nucleic acids of Trypanosoma mega. Nature 1956; 178(4528):308–309.PubMedCrossRefGoogle Scholar
  19. 19.
    Hammond DJ, Gutteridge WE. Purine and pyrimidine metabolism in the Trypanosomatidae. Mol Biochem Parasitol 1984; 13(3):243–261.PubMedCrossRefGoogle Scholar
  20. 20.
    Vasudevan G, Carter NS, Drew ME et al. Cloning of Leishmania nudeoside transporter genes by rescue of a transport-deficient mutant. Proc Natl Acad Sci USA 1998; 95(17):9873–9878.PubMedCrossRefGoogle Scholar
  21. 21.
    Carter NS, Drew ME, Sanchez M et al. Cloning of a novel inosine-guanosine transporter gene from Leishmania donovani by functional rescue of a transport-deficient mutant. J Biol Chem 2000; 275(27):20935–20941.PubMedCrossRefGoogle Scholar
  22. 22.
    Landfear SM. Molecular genetics of nucleoside transporters in Leishmania and African trypanosomes. Biochem Pharmacol 2001; 62(2):149–155.PubMedCrossRefGoogle Scholar
  23. 23.
    Gottlieb M, Dwyer DM. Protozoan parasite of humans: Surface membrane with externally disposed acid phosphatase. Science 1981; 212(4497):939–941.PubMedCrossRefGoogle Scholar
  24. 24.
    Gottlieb M, Dwyer DM. Leishmania donovani: Surface membrane acid phosphatase activity of promastigotes. Exp Parasitol 1981; 52(1):117–128.PubMedCrossRefGoogle Scholar
  25. 25.
    Bates PA, Dwyer DM. Biosynthesis and secretion of acid phosphatase by Leishmania donovani promastigotes. Mol Biochem Parasitol 1987; 26(3):289–296.PubMedCrossRefGoogle Scholar
  26. 26.
    Debrabant A, Bastien P, Dwyer DM. A unique surface membrane anchored purine-salvage enzyme is conserved among a group of primitive eukaryotic human pathogens. Mol Cell Biochem 2001; 220(l–2):109–116.PubMedCrossRefGoogle Scholar
  27. 27.
    Glew RH, Saha AK, Das S et al. Biochemistry of the Leishmania species. Microbiol Rev 1988; 52(4):412–432.PubMedGoogle Scholar
  28. 28.
    Jardim A, Bergeson SE, Shih S et al. Xanthine phosphoribosyltransferase from Leishmania donovani. Molecular cloning, biochemical characterization, and genetic analysis. J Biol Chem 1999; 274(48):34403–34410.PubMedCrossRefGoogle Scholar
  29. 29.
    LaFon SW, Nelson DJ, Berens RL et al. Inosine analogs. Their metabolism in mouse L cells and in Leishmania donovani. J Biol Chem 1985; 260(17):9660–9665.PubMedGoogle Scholar
  30. 30.
    Hassan HF, Coombs GH. Leishmania mexicana: Purine-metabolizing enzymes of amastigotes and promastigotes. Exp Parasitol 1985; 59(2):139–150.PubMedCrossRefGoogle Scholar
  31. 31.
    Ghosh M, Mukherjee T. Stage-specific development of a novel adenosine transporter in Leishmania donovani amastigotes. Mol Biochem Parasitol 2000; 108(1):93–99.PubMedCrossRefGoogle Scholar
  32. 32.
    Hwang HY, Ullman B. Genetic analysis of purine metabolism in Leishmania donovani. J Biol Chem 1997; 272(31):19488–19496.PubMedCrossRefGoogle Scholar
  33. 33.
    Tuttle JV, Krenitsky TA. Purine phosphoribosyltransferases from Leishmania donovani. J Biol Chem 1980; 255(3):909–916.PubMedGoogle Scholar
  34. 34.
    Marr JJ. Pyrazolopyrimidine metabolism in Leishmania and trypanosomes: Significant differences between host and parasite. J Cell Biochem 1983; 22(3): 187–196.PubMedCrossRefGoogle Scholar
  35. 35.
    Fish WR, Marr JJ, Berens RL et al. Inosine analogs as chemotherapeutic agents for African trypanosomes: Metabolism in trypanosomes and efficacy in tissue culture. Antimicrob Agents Chemother 1985; 27(l):33–36.PubMedGoogle Scholar
  36. 36.
    Martinez S, Marr JJ. Allopurinol in the treatment of American cutaneous leishmaniasis. N Engl J Med 1992; 326(11):741–744.PubMedGoogle Scholar
  37. 37.
    Kager PA, Rees PH, Wellde BT et al. Allopurinol in the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg 1981; 75(4):556–559.PubMedCrossRefGoogle Scholar
  38. 38.
    Somoza JR, Chin MS, Focia PJ et al. Crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase from the protozoan parasite Tritrichomonas foetus. Biochemistry 1996; 35(22):7032–7040.PubMedCrossRefGoogle Scholar
  39. 39.
    Schumacher MA, Carter D, Ross DS et al. Crystal structures of Toxoplasma gondii HGXPRTase reveal the catalytic role of a long flexible loop. Nat Struct Biol 1996; 3(10):881–887.PubMedCrossRefGoogle Scholar
  40. 40.
    Focia PJ, Craig IIIrd SP, Nieves-Alicea R et al. A 1.4 A crystal structure for the hypoxanthine phosphoribosyltransferase of Trypanosoma cruzi. Biochemistry 1998; 37(43):15066–15075.PubMedCrossRefGoogle Scholar
  41. 41.
    Freymann DM, Wenck MA, Engel JC et al. Efficient identification of inhibitors targeting the closed active site conformation of the HPRT from Trypanosoma cruzi. Chem Biol 2000; 7(12):957–968.PubMedCrossRefGoogle Scholar
  42. 42.
    Aronov AM, Munagala NR, Ortiz De Montellano PR et al. Rational design of selective submicromolar inhibitors of Tritrichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase. Biochemistry 2000; 39(16):4684–4691.PubMedCrossRefGoogle Scholar
  43. 43.
    Somoza JR, Skillman Jr AG, Munagala NR et al. Rational design of novel antimicrobials: Blocking purine salvage in a parasitic protozoan. Biochemistry 1998; 37(l6):5344–5348.PubMedCrossRefGoogle Scholar
  44. 44.
    Iltzsch MH, Uber SS, Tankersley KO et al. Structure-activity relationship for the binding of nucleoside ligands to adenosine kinase from Toxoplasma gondii. Biochem Pharmacol 1995; 49(10):1501–1512.PubMedCrossRefGoogle Scholar
  45. 45.
    Cohen SS, Plunkett W. The utilization of nucleotides by animal cells. Ann NY Acad Sci 1975; 255(751106-751230-2):269–286.PubMedCrossRefGoogle Scholar
  46. 46.
    Krug EC, Marr JJ, Berens RL. Purine metabolism in Toxoplasma gondii. J Biol Chem1989; 264(18):10601–10607.PubMedGoogle Scholar
  47. 47.
    Pfefferkorn ER, Pfefferkorn LC. Arabinosyl nucleosides inhibit Toxoplasma gondii and allow the selection of resistant mutants. J Parasitol 1976; 62(6):993–999.PubMedCrossRefGoogle Scholar
  48. 48.
    Schwartzman JD, Pfefferkorn ER. Toxoplasma gondii: Purine synthesis and salvage in mutant host cells and parasites. Exp Parasitol 1982; 53(l):77–86.PubMedCrossRefGoogle Scholar
  49. 49.
    Pfefferkorn ER, Pfefferkorn LC. The biochemical basis for resistance to adenine arabinoside in a mutant of Toxoplasma gondii. J Parasitol 1978; 64(3):486–492.PubMedCrossRefGoogle Scholar
  50. 50.
    Iovannisci DM, Ullman B. Characterization of a mutant Leishmania donovani deficient in adenosine kinase activity. Mol Biochem Parasitol 1984; 12(2): 139–151.PubMedCrossRefGoogle Scholar
  51. 51.
    Datta AK, Bhaumik D, Chatterjee R. Isolation and characterization of adenosine kinase from Leishmania donovani. J Biol Chem 1987; 262(12):5515–5521.PubMedGoogle Scholar
  52. 52.
    Chaudhary K, Darling JA, Fohl LM et al. Purine salvage pathways in the apicomplexan parasite Toxoplasma gondii. J Biol Chem 2004; 279(30):31221–31227.PubMedCrossRefGoogle Scholar
  53. 53.
    el Kouni MH, Guarcello V, Al Safarjalani ON et al. Metabolism and selective toxicity of 6-nitrobenzylthioinosine in Toxoplasma gondii. Antimicrob Agents Chemother 1999; 43(10):2437–2443.PubMedGoogle Scholar
  54. 54.
    Yadav V, Chu CK, Rais RH et al. Synthesis, biological activity and molecular modeling of 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase. J Med Chem 2004; 47(8):1987–1996.PubMedCrossRefGoogle Scholar
  55. 55.
    Rais RH, Al Safarjalani ON, Yadav V et al. 6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: Activities and selective toxicities. Biochem Pharmacol 2005; 69(10):1409–1419.PubMedCrossRefGoogle Scholar
  56. 56.
    Mathews II, Erion MD, Ealick SE. Structure of human adenosine kinase at 1.5 A resolution. Biochemistry 1998; 37(45):15607–15620.PubMedCrossRefGoogle Scholar
  57. 57.
    Schumacher MA, Scott DM, Mathews II et al. Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. J Mol Biol 2000; 298(5):875–893.PubMedCrossRefGoogle Scholar
  58. 58.
    Bhaumik D, Datta AK. Immunochemical and catalytic characteristics of adenosine kinase from Leishmania donovani. J Biol Chem 1989; 264(8):4356–4361.PubMedGoogle Scholar
  59. 59.
    Bhaumik D, Datta AK. Reaction kinetics and inhibition of adenosine kinase from Leishmania donovani. Mol Biochem Parasitol 1988; 28(3):181–187.PubMedCrossRefGoogle Scholar
  60. 60.
    Sinha KM, Ghosh M, Das I et al. Molecular cloning and expression of adenosine kinase from Leishmania donovani: Identification of unconventional P-loop motif. Biochem J 1999; 339(Pt3): 667–673.PubMedCrossRefGoogle Scholar
  61. 61.
    Palella TD, Andres CM, Fox IH. Human placental adenosine kinase. Kinetic mechanism and inhibition. J Biol Chem 1980; 255(11):5264–5269.PubMedGoogle Scholar
  62. 62.
    Singh B, Hao W, Wu Z et al. Cloning and characterization of cDNA for adenosine kinase from mammalian (Chinese hamster, mouse, human and rat) species. High frequency mutants of Chinese hamster ovary cells involve structural alterations in the gene. Eur J Biochem 1996; 24l(2):564–571.CrossRefGoogle Scholar
  63. 63.
    Wu LF, Reizer A, Reizer J et al. Nucleotide sequence of the Rhodobacter capsulatus fruK gene, which encodes fructose-1-phosphate kinase: Evidence for a kinase superfamily including both phosphofructokinases of Escherichia coli. J Bacteriol 1991; 173(10):3117–3127.PubMedGoogle Scholar
  64. 64.
    Bork P, Sander C, Valencia A. Convergent evolution of similar enzymatic function on different protein folds: The hexokinase, ribokinase, and galactokinase families of sugar kinases. Protein Sci 1993; 2(l):31–40.PubMedGoogle Scholar
  65. 65.
    Datta R, Das I, Sen B et al. Homology-model-guided site-specific mutagenesis reveals the mechanisms of substrate binding and product-regulation of adenosine kinase from Leishmania donovani. Biochem J 2006; 394(Pt l):35–42.PubMedGoogle Scholar
  66. 66.
    Sigrell JA, Cameron AD, Jones TA et al. Structure of Escherichia coli ribokinase in complex with ribose and dinucleotide determined to 1.8 A resolution: Insights into a new family of kinase structures. Structure 1998; 6(2):183–193.PubMedCrossRefGoogle Scholar
  67. 67.
    Saraste M, Sibbald PR, Wittinghofer A. The P-loop—a common motif in ATP-and GTP-binding proteins. Trends Biochem Sci 1990; 15(11):430–434.PubMedCrossRefGoogle Scholar
  68. 68.
    Muller CW, Schulz GE. Structure of the complex between adenylate kinase from Escherichia coli and the inhibitor Ap5A refined at 1.9 A resolution. A model for a catalytic transition state. J Mol Biol 1992; 224(1):159–177.PubMedCrossRefGoogle Scholar
  69. 69.
    Matte A, Tari LW, Delbaere LT. How do kinases transfer phosphoryl groups? Structure1998; 6(4):413–419.PubMedCrossRefGoogle Scholar
  70. 70.
    Story RM, Steitz TA. Structure of the recA protein-ADP complex. Nature 1992; 355(6358):374–376.PubMedCrossRefGoogle Scholar
  71. 71.
    Berchtold H, Reshetnikova L, Reiser CO et al. Crystal structure of active elongation factor Tu reveals major domain rearrangements. Nature 1993; 365(6442):126–132.PubMedCrossRefGoogle Scholar
  72. 72.
    Muegge I, Schweins T, Langen R et al. Electrostatic control of GTP and GDP binding in the oncoprotein p21ras. Structure 1996; 4(4):475–489.PubMedCrossRefGoogle Scholar
  73. 73.
    Smith CM, Radzio-Andzelm E, Madhusudan et al. The catalytic subunit of cAMP-dependent protein kinase: Prototype for an extended network of communication. Prog Biophys Mol Biol 1999; 71(3-4):313–341.PubMedCrossRefGoogle Scholar
  74. 74.
    Van der Ploeg LH. Discontinuous transcription and splicing in trypanosomes. Cell 1986; 47(4):479–480.PubMedCrossRefGoogle Scholar
  75. 75.
    Darling JA, Sullivan Jr WJ, Carter D et al. Recombinant expression, purification, and characterization of Toxoplasma gondii adenosine kinase. Mol Biochem Parasitol 1999; 103(l):15–23.PubMedCrossRefGoogle Scholar
  76. 76.
    Carret C, Delbecq S, Labesse G et al. Characterization and molecular cloning of an adenosine kinase from Babesia canis rossi. Eur J Biochem 1999; 265(3):1015–1021.PubMedCrossRefGoogle Scholar
  77. 77.
    Spychala J, Datta NS, Takabayashi K et al. Cloning of human adenosine kinase cDNA: Sequence similarity to microbial ribokinases and fructokinases. Proc Natl Acad Sci USA 1996; 93(3):1232–1237.PubMedCrossRefGoogle Scholar
  78. 78.
    Datta R, Das I, Sen B et al. Mutational analysis of the active-site residues crucial for catalytic activity of adenosine kinase from Leishmania donovani. Biochem J 2005; 387(Pt 3):591–600.PubMedGoogle Scholar
  79. 79.
    Hawkins CF, Bagnara AS. Adenosine kinase from human erythrocytes: Kinetic studies and characterization of adenosine binding sites. Biochemistry 1987; 26(7): 1982–1987.PubMedCrossRefGoogle Scholar
  80. 80.
    Chakraborty A, Das I, Datta R et al. A single-domain cyclophilin from Leishmania donovani reactivates soluble aggregates of adenosine kinase by isomerase-independent chaperone function. J Biol Chem 2002; 277(49):47451–47460.PubMedCrossRefGoogle Scholar
  81. 81.
    Chakraborty A, Sen B, Datta et al. Isomerase-independent chaperone function of cyclophilin ensures aggregation prevention of adenosine kinase both in vitro and under in vivo conditions. Biochemistry 2004; 43(37): 11862–11872.PubMedCrossRefGoogle Scholar
  82. 82.
    Sen B, Chakraborty A, Datta R et al. Reversal of ADP-Mediated Aggregation of Adenosine Kinase by Cyclophilin Leads to Its Reactivation. Biochemistry 2006; 45(1):263–271.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Alok Kumar Datta
    • 1
  • Rupak Datta
    • 2
  • Banibrata Sen
    • 2
  1. 1.Emeritus Scientist, CSIR (Govt. of India)Indian Institute of Chemical BiologyKolkata 700032India
  2. 2.Division of Infectious DiseasesIndian Institute of Chemical Biology JadavpurKolkataIndia

Personalised recommendations