Skip to main content

Advertisement

SpringerLink
Log in

Structural analysis of trypanosomal sirtuin: an insight for selective drug design

  • Short Communication
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

The infectious disease burden imposed by trypanosomatidae family continues to create burden in countries that are least equipped to bring new medicines to the clinic. For sickness caused by this family of parasites (African trypanosomiasis, Chagas disease, and leishmaniasis) no vaccines are available, and currently available drugs suffer from insufficient efficacy, excessive toxicity, and steady loss of effectiveness due to resistance. Availability of the genome sequence of pathogens of this family offers a unique avenue for the identification of novel common drug targets for all three pathogens. Sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases are remarkably conserved throughout evolution from archaebacteria to eukaryotes and plays an important role in trypanosomatidae biology and virulence. In order to gain insight for selective drug design, three-dimensional (3D) models of L. major, L. infantum, T. brucie, and T. cruzi sirtuin were constructed by homology modeling and compared with human sirtuin. The molecular electrostatic potentials and cavity depth analysis of these models suggest that the inhibitor binding catalytic domain has various minor structural differences in the active site of trypanosomal and human sirtuin, regardless of sequence similarity. These studies have implications for designing effective strategies to identify inhibitors that can be developed as novel broad-spectrum antitrypanosomal drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Parsons M, Worthey EA, Ward PN et al (2005) Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genomics 6: 127. doi:10.1186/1471-2164-6-127

    Article  PubMed  Google Scholar 

  2. Vickerman K (1985) Developmental cycles and biology of pathogenic trypanosomes. Br Med Bull 41: 105–114

    CAS  PubMed  Google Scholar 

  3. Punukollu G, Gowda RM, Khan IA et al (2006) Clinical aspects of the Chagas’ heart disease. Int J Cardiol 115: 279–283. doi:10.1016/j.ijcard.2006.03.004

    Article  Google Scholar 

  4. Silva AA, Roffê E, Marino AP et al (1999) Chagas’ disease encephalitis: intense CD8+ lymphocytic infiltrate is restricted to the acute phase, but is not related to the presence of Trypanosoma cruzi antigens. Clin Immunol 92: 56–66. doi:10.1006/clim.1999.4716

    Article  CAS  PubMed  Google Scholar 

  5. da Silveira ABM, Lemos EM, Adad SJ et al (2007) Megacolon in Chagas disease: a study of inflammatory cells, enteric nerves, and glial cells. Hum Pathol 38: 1256–1264. doi:10.1016/j.humpath.2007.01.020

    Article  PubMed  Google Scholar 

  6. Zubrzycki IZ (2002) Homology modeling and molecular dynamics study of NAD-dependent glycerol-3-phosphate dehydrogenase from Trypanosoma brucei rhodesiense, a potential target enzyme for anti-sleeping sickness drug development. Biophys J 82: 2906–2915. doi:10.1016/S0006-3495(02)75631-2

    Article  CAS  PubMed  Google Scholar 

  7. Guerin PJ, Olliaro P, Sundar S et al (2002) Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2: 494–501. doi:10.1016/S1473-3099(02)00347-X

    Article  PubMed  Google Scholar 

  8. Davies CR, Kaye P, Croft SL et al (2003) Leishmaniasis:new approaches to disease control. BMJ 326: 377–382. doi:10.1136/bmj.326.7385.377

    Article  PubMed  Google Scholar 

  9. Barrett MP, Gilbert IH (2002) Perspectives for new drugs against Trypanosomiasis and Leishmaniasis. Curr Top Med Chem 2: 471–482. doi:10.2174/1568026024607427

    Article  CAS  PubMed  Google Scholar 

  10. Barrett MP, Coombs GH, Mottram JC (1999) Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. Trends Microbiol 7: 82–88. doi:10.1016/S0966-842X(98)01433-4

    Article  CAS  PubMed  Google Scholar 

  11. Dali-Youcef N, Lagouge M, Froelich S et al (2007) Sirtuins: the magnificent seven’, function, metabolism and longevity. Ann Med 39: 335–345. doi:10.1080/07853890701408194

    Article  CAS  PubMed  Google Scholar 

  12. Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273: 793–798. doi:10.1006/bbrc.2000.3000

    Article  CAS  PubMed  Google Scholar 

  13. Yahiaoui B, Taibi A, Ouaissi A (1996) A Leishmania major protein with extensive homology to silent information regulator 2 of Saccharomyces cerevisiae. Gene 169: 115–118. doi:10.1016/0378-1119(95)00785-7

    Article  CAS  PubMed  Google Scholar 

  14. Vergnes B, Sereno D, Madjidian-Sereno N et al (2002) Cytoplasmic SIR2 homologue overexpression promotes survival of Leishmania parasites by preventing programmed cell death. Gene 296: 139–150. doi:10.1016/S0378-1119(02)00842-9

    Article  CAS  PubMed  Google Scholar 

  15. Vergnes B, Vanhille L, Ouaissi A et al (2005) Stage-specific antileishmanial activity of an inhibitor of SIR2 histone deacetylase. Acta Trop 94: 107–115. doi:10.1016/j.actatropica.2005.03.004

    Article  CAS  PubMed  Google Scholar 

  16. Sereno D, Alegre AM, Silvestre R et al (2005) In vitro antileishmanial activity of Nicotinamide. Antimicrob Agents Chemother 49: 808–812. doi:10.1128/AAC.49.2.808-812.2005

    Article  CAS  PubMed  Google Scholar 

  17. García-Salcedo JA, Gijón P, Nolan DP et al (2003) A chromosomal SIR2 homologue with both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei. EMBO J 22: 5851–5862. doi:10.1093/emboj/cdg553

    Article  PubMed  Google Scholar 

  18. MOE software package, version 06, Chemical Computing Group Inc., Montreal, Canada

  19. SYBYL software package, version 7.3, Tripos Associates Inc., 1699, S. Hanley Rd., St. Louis, MO 631444, USA

  20. Altschul SF, Gish W, Miller W et al (1990) Basic local alignment search tool. J Mol Biol 215: 403–410

    CAS  PubMed  Google Scholar 

  21. Berman HM, Westbrook J, Feng Z et al (2000) The protein data bank. Nucleic Acids Res 28: 235–242. doi:10.1093/nar/28.1.235

    Article  CAS  PubMed  Google Scholar 

  22. Laskowski RA, MacArthur MW, Moss DS et al (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst 26: 283–291. doi:10.1107/S0021889892009944

    Article  CAS  Google Scholar 

  23. Lüthy R, Bowie JU, Eisenberg D (1992) Assessment of protein models with 3D-profiles. Nature 356: 83–85. doi:10.1038/356083a0

    Article  PubMed  Google Scholar 

  24. Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a Sir2 enzyme. Mol Cell 17: 855–868. doi:10.1016/j.molcel.2005.02.022

    Article  CAS  PubMed  Google Scholar 

  25. Zhao K, Chai X, Marmorstein R (2003) Structure of the yeast Hst2 protein deacetylase in ternary complex with 2′-O-acetyl ADP ribose and histone peptide. Nat Struct Biol 11: 1403–1411. doi:10.1016/j.str.2003.09.016

    Article  CAS  Google Scholar 

  26. Finnin MSDJ, Pavletich NP (2001) Structure of the histone deacetylase SIRT2. Nat Struct Biol 8: 621–625. doi:10.1038/89668

    Article  CAS  PubMed  Google Scholar 

  27. Sanders BD, Zhao K, Slama JT et al (2007) Structural basis for nicotinamide inhibition and base exchange in Sir2 enzymes. Mol Cell 25: 463–472. doi:10.1016/j.molcel.2006.12.022

    Article  CAS  PubMed  Google Scholar 

  28. Bhattacharrjee AK, Karle JM (1998) Functional correlation of molecular electronic properties with potency of synthetic carbinolamines antimalarial agents. Bioorg Med Chem 8: 1927–1933. doi:10.1016/S0968-0896(98)00146-1

    Article  Google Scholar 

  29. Bhattacharjee AK, Karle JM (1999) Stereoelectronic properties of antimalarial artemisinin analogues in relation to neurotoxicity. Chem Res Toxicol 12: 422–428. doi:10.1021/tx9802116

    Article  CAS  PubMed  Google Scholar 

  30. Kadam RU, Tavares J, Kiran VM, Cordeiro A, Ouaissi A, Roy N (2008) Structure function analysis of leishmania sirtuin: an ensemble of in silico and biochemical studies. Chem Biol Drug Des 71: 501–106. doi:10.1111/j.1747-0285.2008.00652.x

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S Nagar, Mohali, Punjab, 160062, India

    Simranjeet Kaur, Amol V. Shivange & Nilanjan Roy

Authors
  1. Simranjeet Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amol V. Shivange
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nilanjan Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nilanjan Roy.

Electronic supplementary material

Below are the Electronic Supplementary Materials.

ESM 1 (PDF 707 kb)

ESM 2 (PDF 310 kb)

ESM 3 (PDF 1.28 mb)

ESM 4 (PDF 430 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaur, S., Shivange, A.V. & Roy, N. Structural analysis of trypanosomal sirtuin: an insight for selective drug design. Mol Divers 14, 169–178 (2010). https://doi.org/10.1007/s11030-009-9147-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-009-9147-7

Keywords

Search

Navigation