DNA Topoisomerases of Leishmania: The Potential Targets for Anti-Leishmanial Therapy

  • Benu Brata Das
  • Agneyo Ganguly
  • Hemanta K. Majumder
Part of the Advances In Experimental Medicine And Biology book series (AEMB, volume 625)


Protozoan parasites of the genus Leishmania cause severe diseases that threaten human beings, both for the high mortality rates involved and the economic loss resulting from morbidity, primarily in the tropical and subtropical areas. This ancient eukaryote shows variable genetic diversity in their life cycle, wherein DNA topoisomerases play a key role in cellular processes affecting the topology and organization of intracellular DNA. Kinetoplastid topoisomerases offer most attractive targets for their structural diversity from other eukaryotic counterparts and their indispensable function in cell biology. Therefore, understanding the biology of kinetoplastid topoisomerases and the components and steps involved in this intricate process provide opportunities for target based drug designing against protozoan parasitic diseases.


Visceral Leishmaniasis Leishmania Donovani Sodium Stibogluconate Pentavalent Antimonial Kinetoplastid Parasite 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006; 19:111–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Wang JC. Cellular roles of DNA topoisomerases: A molecular perspective. Nat Rev Mol Cell Biol 2002; 6:430–40.CrossRefGoogle Scholar
  3. 3.
    Champoux JJ. DNA topoisomerases: Structure, function, and mechanism. Annu Rev Biochem 2001; 70:369–413.PubMedCrossRefGoogle Scholar
  4. 4.
    Ferguson LR, Baguley BC. Topoisomerase II enzymes and mutagenicity. Environ Mol Mutagen 1994; 24:245–261.PubMedCrossRefGoogle Scholar
  5. 5.
    Liu LF. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 1989; 58:351–75.PubMedCrossRefGoogle Scholar
  6. 6.
    Burri C, Bodley AL, Shapiro TA. Topoisomerases in kinetoplastids. Parasitol Today 1996; 6:226–31.CrossRefGoogle Scholar
  7. 7.
    Bjornsti MA, Wang JC. Expression of yeast DNA topoisomerase I can complement a conditional-lethal DNA topoisomerase I mutation in Escherichia coli. Proc Natl Acad Sci USA 1987; 84:8971–8975.PubMedCrossRefGoogle Scholar
  8. 8.
    Stewart L, Ireton GC, Champoux JJ. Reconstitution of human topoisomerase I by fragment complementation. J Mol Biol 1997; 269:355–372.PubMedCrossRefGoogle Scholar
  9. 9.
    Berger JM. Structure of DNA topoisomerases. Biochim Biophys Acta 1998; 1400:3–18.PubMedGoogle Scholar
  10. 10.
    Bakshi RP, Galande S, Muniyappa K. Functional and regulatory characteristics of eukaryotic type II DNA topoisomerases. Crit Rev Biochem Mol Biol 2001; 36:1–37.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang JC. DNA topoisomerases: Why so many? J Biol Chem 1991; 266:6659–6662.PubMedGoogle Scholar
  12. 12.
    Broxterman HJ, Georgopapadakou N. Cancer research 2001: Drug resistance, new targets and drug combinations. Drug Resist Updat 2001; 4:197–209.PubMedCrossRefGoogle Scholar
  13. 13.
    Nitiss JL. DNA topoisomerases in cancer chemotherapy: Using enzymes to generate selective DNA damage. Curr Opin Investig Drugs 2002; 3:1512–1516.PubMedGoogle Scholar
  14. 14.
    Denny WA, Baguley BC. Dual Topoisomerase I/II Inhibitors in Cancer Therapy Curr. Top Med Chem 2003; 3:339–353.CrossRefGoogle Scholar
  15. 15.
    Shapiro TA. Inhibition of topoisomerases in African trypanosomes. Acta Trop 1993; 54:251–260.PubMedCrossRefGoogle Scholar
  16. 16.
    Bodley AL, Wani MC, Wall ME et al. Antitrypanosomal activity of camptothecin analogs. Structure-activity correlations. Biochem Pharmacol 1995; 50:937–942.PubMedCrossRefGoogle Scholar
  17. 17.
    Bearden DT, Danziger LH. Mechanism of action of and resistance to quinolones. Pharmacotherapy 2001; 21:224S–232S.PubMedCrossRefGoogle Scholar
  18. 18.
    Chakraborty AK, Majumder HK. Mode of action of pentavalent antimonials: Specific inhibition of type I DNA topoisomerase of Leishmania donovani. Biochem Biophys Res Commun 1988; 152:605–611.PubMedCrossRefGoogle Scholar
  19. 19.
    Chakraborty AK et al. A type I DNA topoisomerase from the kinetoplast hemoflagellate Leishmania donovani. Ind J Biochem Biophys 1993; 30:257–263.Google Scholar
  20. 20.
    Riou GF et al. A type I DNA topoisomerase from Trypanosoma cruzi. Eur J Biochem 1983; 134:479–484.PubMedCrossRefGoogle Scholar
  21. 21.
    Melendy T, Ray DS. Purification and nuclear localization of type I topoisomerase from Crithidia fasciculata. Mol Biochem Parasitol 1987; 24:215–225.PubMedCrossRefGoogle Scholar
  22. 22.
    Bodley AL, Shapiro TA. Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania. Proc Natl Acad Sci USA 1995; 92:3726–3730.PubMedCrossRefGoogle Scholar
  23. 23.
    Broccoli S, Marquis JF, Papadopoulou B et al. Characterization of a Leishmania donovani gene encoding a protein that resembles a type IB topoisomerase. Nucleic Acids Res 1999; 27:2745–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Champoux JJ. Domains of human topoisomerase I and associated functions. Prog Nucleic Acid Res Mol Biol 1998; 60:111–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Das A, Dasgupta A, Sengupta T et al. Topoisomerases of kinetoplastid parasites as potential chemotherapeutic targets. Trends Parasitol 2004; 8:381–387.CrossRefGoogle Scholar
  26. 26.
    Bodley AL, Shapiro TA. Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania. Proc Natl Acad Sci USA 1995; 92:3726–3730.PubMedCrossRefGoogle Scholar
  27. 27.
    Villa H, OteroMarcos AR, Reguera RM et al. A novel active DNA topoisomerase I in Leishmania donovani. J Biol Chem 2003; 278:3521–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Stewart L, Ireton GC, Champoux JJ. The domain organization of human Topoisomerase I. J Biol Chem 1996; 271:7602–8.PubMedCrossRefGoogle Scholar
  29. 29.
    D’Arpa P, Machlin PS, Ratrie IIIrd H et al. cDNA cloning of human DNA Topoisomerase I: Catalytic activities of a 67.7kDa carboxy-terminal fragment. Proc Natl Acad Sci USA 1988; 85:2543–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Liu LF, Miller KG. Eukaryotic DNA topoisomerases: Two forms of type I DNA topoisomerases from HeLa cell nuclei. Proc Natl Acad Sci USA 1981; 78:3487–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Das BB, Sen N, Ganguly A et al. Reconstitution and functional characterization of the unusual bi-subunit type I DNA topoisomerase from Leishmania donovani. FEBS Lett 2004; 565:81–88.PubMedCrossRefGoogle Scholar
  32. 32.
    Das BB, Sen N, Dasgupta SB et al. N-terminal region of the large subunit of Leishmania donovani bisubunit topoisomerase I is involved in DNA relaxation and interaction with the smaller subunit. J Biol Chem 2005; 280:16335–44.PubMedCrossRefGoogle Scholar
  33. 33.
    Bakshi RP, Shapiro TA. RNA interference of Trypanosoma brucei topoisomerase IB: Both sub-units are essential. Mol Biochem Parasitol 2004; 136:249–55.PubMedCrossRefGoogle Scholar
  34. 34.
    Davies DR, Mushtaq A, Interthal H et al. The structure of the transition state of the heterodimeric topoisomerase I of Leishmania donovani as a vanadate complex with nicked DNA. J Mol Biol 2006; 357:1202–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Melendy T, Shelina C, Ray DS. Localization of a type II DNA topoisomerase to two sites at the periphery of the kinetoplast DNA of Crithidia fasciculata. Cell 1988; 55:1083–1088.PubMedCrossRefGoogle Scholar
  36. 36.
    Das A, Dasgupta A, Sharma S et al. Characterisation of the gene encoding type II DNA topoisomerase from Leishmania donovani: A key molecular target in antileishmanial therapy. Nucleic Acids Res 2001; 29:1844–1851.PubMedCrossRefGoogle Scholar
  37. 37.
    Gaziova I, Lukes J. Mitochondrial and nuclear localization of topoisomerase II in the flagellate Bodo saltans (Kinetoplastida), a species with noncatenated kinetoplast DNA. J Biol Chem 2003; 278:10900–10907.PubMedCrossRefGoogle Scholar
  38. 38.
    Lynn R, Giaever G, Swanberg SL et al. Tandem regions of yeast DNA topoisomerase II share homology with different subunits of bacterial gyrase. Science 1986; 233:647–649.PubMedCrossRefGoogle Scholar
  39. 39.
    Liu LF, Liu CC, Alberts BM. T4 DNA topoisomerase: A new ATP dependent enzyme for T4 bacteriophage DNA replication. Nature 1979; 281:456–461.PubMedCrossRefGoogle Scholar
  40. 40.
    Seasholtz AF, Greenberg GR. Identification of bacteriophage T4 gene 60 product and a role for this protein in DNA topoisomerase. J Biol Chem 1983; 258:1221–1226.PubMedGoogle Scholar
  41. 41.
    Sengupta T, Mukherjee M, Mandal CN et al. Functional dissection of the C-terminal domain of type II DNA topoisomerase of kinetoplastid hemoflagellate Leishmania donovani. Nucleic Acids Res 2003; 31:5305–5316.PubMedCrossRefGoogle Scholar
  42. 42.
    Sengupta T, Mukherjee M, Das R et al. characterization of the DNA-binding domain and identification of the active site residue in the gyr A half of Leishmania donovani topoisomerase II. Nucleic Acids Res 2005; 33:2364–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Sengupta T, Mukherjee M, Das A et al. Characterization of the ATPase activity of topoisomerase II from L. donovani and identification of the residues conferring resistance to etoposide. Biochem J 2005; 390:419–26.PubMedCrossRefGoogle Scholar
  44. 44.
    Campbell S, Maxwell A. The ATP-operated clamp of human DNA topoisomerase IIalpha: Hyper-stimulation of ATPase by “piggy-back” binding. J Mol Biol 2002; 320:171–188.PubMedCrossRefGoogle Scholar
  45. 45.
    Tsai-Pflugfelder M, Liu LF, Liu AA et al. Cloning and sequencing C-DNA encoding human topoisomerase II and localization of the gene to chromosome region 1988; 17q21–22.Google Scholar
  46. 46.
    Vilian N, Tsai-Pflugfelder M, Benoit A et al. Modulation of drug sensitivity in yeast cells by the ATP-binding domain of human DNA topoisomerase II alpha. Nucleic Acids Res 2003; 31:5714–5722.CrossRefGoogle Scholar
  47. 47.
    Wang JC. DNA topoisomerase as targets of therapeutics: An overview. Adv Pharmacol 1994; 29A:1–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Chakraborty AK, Majumder HK. Mode of action of pentavalent antimonials: Specific inhibition of type I DNA topoisomerase of Leishmania donovani. Biochem Biophys Res Commun 1988; 152:605–11.PubMedCrossRefGoogle Scholar
  49. 49.
    Lucumi A, Robledo S, Gama V et al. Sensitivity of Leishmania viannia panamensis to pentavalent antimony is correlated with the formation of cleavable DNA-protein complexes. Antimicrob Agents Chemother 1998; 42:1990–5.PubMedGoogle Scholar
  50. 50.
    Marquis JF, Hardy I, Olivier M. Topoisomerase I amino acid substitutions, Glyl85Arg and Asp325Glu, confer camptothecin resistance in Leishmania donovani. Antimicrob Agents Chemother 2005; 49:1441–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Sen N, Das BB, Ganguly A et al. Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani. Cell Death Differ 2004; 11:924–36.PubMedCrossRefGoogle Scholar
  52. 52.
    Sen N, Das BB, Ganguly A et al. Camptothecin-induced imbalance in intracellular cation homeostasis regulates programmed cell death in unicellular hemoflagellate Leishmania donovani. J Biol Chem 2004; 279:52366–75.PubMedCrossRefGoogle Scholar
  53. 53.
    Slunt KM, Grace JM, Macdonald TL et al. Effect of mitonafide analogs on topoisomerase II of Leishmania chagasi. Antimicrob Agents Chemother 1996; 40:706–709.PubMedGoogle Scholar
  54. 54.
    Werbovetz KA, Spoors PG, Pearson RD et al. Cleavable complex formation in Leishmania chagasi treated with anilinoacridines. Mol Biochem Parasitol 1994; 65:1–10.PubMedCrossRefGoogle Scholar
  55. 55.
    Gamage SA, Figgitt DP, Wojcik SJ et al. Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1’-substituted 9-anilinoacridines. J Med Chem 1997; 40:2634–42.PubMedCrossRefGoogle Scholar
  56. 56.
    Werbovetz KA, Lehnert EK, Macdonald TL et al. Cytotoxicity of acridine compounds for Leishmania promastigotes in vitro. Antimicrob Agents Chemother 1992; 36:495–497.PubMedGoogle Scholar
  57. 57.
    Ray S, Majumder HK, Chakravarty AK et al. Amarogentin, a naturally occurring secoiridoid glycoside and a newly recognized inhibitor of topoisomerase I from Leishmania donovani. J Natl Prod 1996; 59:27–29.CrossRefGoogle Scholar
  58. 58.
    Medda S, Mukhopadhyay S, Basu MK. Evaluation of the in-vivo activity and toxicity of amarogentin, an antileishmanial agent, in both liposomal and niosomal forms. J Antimicrob Chemother 1999; 44:791–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Ray S, Sadhukhan PK, Mandal NB et al. Dual inhibition of DNA topoisomerases of Leishmania donovani by novel Indolyl quinolines. Biochem Biophys Res Commun 1997; 230:171–175.PubMedCrossRefGoogle Scholar
  60. 60.
    Ray S, Hazra B, Mittra B et al. Diospyrin, a bisnaphthoquinone: A novel inhibitor of type I DNA topoisomerase of Leishmania donovani. Mol Pharmacol 1998; 54:994–999.PubMedGoogle Scholar
  61. 61.
    Chowdhury AR, Mandal S, Goswami A et al. Dihydrobetulinic acid induces apoptosis in Leishmania donovani by primarily targeting DNA topoisomerase I and II: Implications in antileishmanial therapy. Mol Med 2003; 9:26–36.PubMedGoogle Scholar
  62. 62.
    Mittra B, Saha H, Chowdhury AR et al. Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis. Mol Med 2000; 6:527–541.PubMedCrossRefGoogle Scholar
  63. 63.
    Das BB, Sen N, Roy A et al. Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: Activity of flavones against camptothecin-resistant topoisomerase I. Nucleic Acids Res 2006; 34:21–32.CrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Benu Brata Das
    • 1
  • Agneyo Ganguly
    • 1
  • Hemanta K. Majumder
    • 2
  1. 1.Department of Molecular ParasitologyIndian Institute of Chemical BiologyKolkataIndia
  2. 2.Molecular Parasitology LaboratoryIndian Institute of Chemical BiologyKolkata-700032

Personalised recommendations