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The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis.

Buschiazzo A, Amaya MF, Cremona ML, Frasch AC, Alzari PM
Mol Cell 10 757-68 (2002)
Related entries: 1ms0, 1ms1, 1ms3, 1ms4, 1ms5, 1ms8, 1ms9

Cited: 127 times
EuropePMC logo PMID: 12419220

Abstract

Trans-sialidases (TS) are GPI-anchored surface enzymes expressed in specific developmental stages of trypanosome parasites like Trypanosoma cruzi, the etiologic agent of Chagas disease, and T. brucei, the causative agent of sleeping sickness. TS catalyzes the transfer of sialic acid residues from host to parasite glycoconjugates through a transglycosidase reaction that appears to be critical for T. cruzi survival and cell invasion capability. We report here the structure of the T. cruzi trans-sialidase, alone and in complex with sugar ligands. Sialic acid binding is shown to trigger a conformational switch that modulates the affinity for the acceptor substrate and concomitantly creates the conditions for efficient transglycosylation. The structure provides a framework for the structure-based design of novel inhibitors with potential therapeutic applications.

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Reviews citing this publication (19)

  1. Trypanosoma cruzi surface mucins: host-dependent coat diversity. Buscaglia CA, Campo VA, Frasch AC, Di Noia JM. Nat Rev Microbiol 4 229-236 (2006)
  2. Recent structural insights into the expanding world of carbohydrate-active enzymes. Davies GJ, Gloster TM, Henrissat B. Curr Opin Struct Biol 15 637-645 (2005)
  3. Sialic acid metabolism and sialyltransferases: natural functions and applications. Li Y, Chen X. Appl Microbiol Biotechnol 94 887-905 (2012)
  4. Glycosaminoglycans in infectious disease. Kamhi E, Joo EJ, Dordick JS, Linhardt RJ. Biol Rev Camb Philos Soc 88 928-943 (2013)
  5. Multigene families in Trypanosoma cruzi and their role in infectivity. De Pablos LM, Osuna A. Infect Immun 80 2258-2264 (2012)
  6. The trans-sialidase, the major Trypanosoma cruzi virulence factor: Three decades of studies. Freire-de-Lima L, Fonseca LM, Oeltmann T, Mendonça-Previato L, Previato JO. Glycobiology 25 1142-1149 (2015)
  7. T rypanosoma cruzi trans-sialidase as a multifunctional enzyme in Chagas' disease. Dc-Rubin SS, Schenkman S. Cell Microbiol 14 1522-1530 (2012)
  8. Role of Trypanosoma cruzi Trans-sialidase on the Escape from Host Immune Surveillance. Nardy AF, Freire-de-Lima CG, Pérez AR, Morrot A. Front Microbiol 7 348 (2016)
  9. A survey of the year 2002 commercial optical biosensor literature. Rich RL, Myszka DG. J Mol Recognit 16 351-382 (2003)
  10. Parasite-host glycan interactions during Trypanosoma cruzi infection: trans-Sialidase rides the show. Campetella O, Buscaglia CA, Mucci J, Leguizamón MS. Biochim Biophys Acta Mol Basis Dis 1866 165692 (2020)
  11. Perspectives on the Trypanosoma cruzi-host cell receptor interactions. Villalta F, Scharfstein J, Ashton AW, Tyler KM, Guan F, Mukherjee S, Lima MF, Alvarez S, Weiss LM, Huang H, Machado FS, Tanowitz HB. Parasitol Res 104 1251-1260 (2009)
  12. Sialoglycans in protozoal diseases: their detection, modes of acquisition and emerging biological roles. Chava AK, Bandyopadhyay S, Chatterjee M, Mandal C. Glycoconj J 20 199-206 (2004)
  13. The chemistry and biology of trypanosomal trans-sialidases: virulence factors in Chagas disease and sleeping sickness. Schauer R, Kamerling JP. Chembiochem 12 2246-2264 (2011)
  14. Molecular analysis of early host cell infection by Trypanosoma cruzi. Villalta F, Madison MN, Kleshchenko YY, Nde PN, Lima MF. Front Biosci 13 3714-3734 (2008)
  15. Trypanosoma cruzi trans-sialidase as a drug target against Chagas disease (American trypanosomiasis). Miller BR, Roitberg AE. Future Med Chem 5 1889-1900 (2013)
  16. Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease. Bowles WHD, Gloster TM. Front Mol Biosci 8 705133 (2021)
  17. Modulation of Cell Sialoglycophenotype: A Stylish Mechanism Adopted by Trypanosoma cruzi to Ensure Its Persistence in the Infected Host. Freire-de-Lima L, da Fonseca LM, da Silva VA, da Costa KM, Morrot A, Freire-de-Lima CG, Previato JO, Mendonça-Previato L. Front Microbiol 7 698 (2016)
  18. Sialidase Inhibitors with Different Mechanisms. Keil JM, Rafn GR, Turan IM, Aljohani MA, Sahebjam-Atabaki R, Sun XL. J Med Chem 65 13574-13593 (2022)
  19. Recent developments in trans-sialidase inhibitors of Trypanosoma cruzi. Kashif M, Moreno-Herrera A, Lara-Ramirez EE, Ramírez-Moreno E, Bocanegra-García V, Ashfaq M, Rivera G. J Drug Target 25 485-498 (2017)

Articles citing this publication (106)



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