THE PLASMODIUM GLUTATHIONE S-TRANSFERASE - Bioinformatics Characterization and Classification into the Sigma Class

Emilee E. Colón-Lorenzo, Adelfa E. Serrano, Hugh B. Nicholas Jr, Troy Wymore, Alexander J. Ropelewski, Ricardo González-Méndez


Malaria is a global health problem caused by Plasmodium parasites. Glutathione S-transferase (GST) is involved in the conjugation of glutathione to drugs and toxic compounds. It is postulated that GST plays an important role in the development of drug resistance. The three-dimensional (3D) structure of Plasmodium falciparum GST (PfGST) has been solved and previous work indicates that the PfGST cannot be assigned to any of the known GST classes. We performed sequence analyses, structural modeling and alignment of GSTs from Plasmodium to known structures of the GST from other organisms to classify PfGST into a GST family. Sequence alignments using ClustalW, motif analysis using MEME, and phylogenetic analysis using MEGA4, of Plasmodium GSTs and 38 other GST sequences were done. The alignments and motifs show a close relationship to the alpha and sigma class of GSTs. The phylogenetic analysis places the Plasmodium GSTs in the sigma class. A comparison of PfGST with known structures of GSTs reveals high structural similarity to the sigma class GST, in particular within the H-site and C-terminus of the protein. These findings allow PfGST to be classified into the sigma class GSTs. These data may open new avenues for the development of novel antimalarials.


  1. Bailey, T.L., Elkan, C., 1994. "Fitting a mixture model by expectation maximization to discover motifs in biopolymers", Proceedings of the Second International Conference on Intelligent Systems for Molecular Biology, pp. 28-36, AAAI Press, Menlo Park, California.
  2. Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E., 2000. The Protein Data Bank Nucleic Acids Research, 28 pp. 235-242.
  3. Burmeister, C., Perbandt, M., Betzel, Ch., Walter, R. D., Liebau, E., 2003. Crystallization and preliminary Xray diffraction studies of the glutathione S-transferase from Plasmodium falciparum. Acta Crystallogr. D Biol. Crystallogr. 59, 1469-1471.
  4. Carlton, J.M., Adams, J.H., Silva, J.C., et al., 2008. Comparative genomics of the neglected human malaria parasite Plasmodium vivax. Nature 455:757- 763.
  5. Deponte, M., Becker, K., 2005. Glutathione S-transferase from malarial parasites: structural and functional aspects. Methods Enzymol. 401:240-252.
  6. Dubois, V.L., Platel, D.F., 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.
  7. Federici, L., Sterzo, C.L., Pezzola, S., Matteo, A.D., Scaloni, F., Federici, G., Caccuri, A.M. 2009. Structural basis for the binding of the anticancer compound 6-(7-Nitro-2,1,3-Benzoxadiazol-4- Ylthio)Hexanol to human glutathione S-transferases. Cancer Research 69:20.
  8. Filomeni G., Turella, P., Dupuis, M.L., Forini, O., Ciriolo, M.R., Cianfriglia, M., Pezzola, S., Federici, G., Caccuri, A.M. 2008. 6-(7-Nitro-2,1,3-Benzoxadiazol4-Ylthio)Hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)- associated protein 1-mediated MDR in small cell lung cancer. Molecular cancer therapeutics 7(2).
  9. Fritz-Wolf, K., Becker, A., Rahlfs, S., Harwaldt, P., Schirmer, R. H., Kabsch, W., Becker, K., 2003. X-ray structure of glutathione S-transferase from the malarial parasite Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 100, 13821-13826.
  10. Higgins, D., Thompson, J., Gibson, T., Thompson, J.D., Higgins, D.G., Gibson, T.J., 1994. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673-4680.
  11. Humphrey, W., Dalke, A., Schulten, K., 1996. VMD - Visual Molecular Dynamics. J. Molec. Graphics, vol. 14, pp. 33-38
  12. Meierjohann, S., Walter, R.D., Muller, S. 2002. Regulation of intracellular glutathione levels in erythrocytes infected with chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. Biochem J. Dec 15: 368, 761-8.
  13. Nicholas, K.B., Nicholas, H.B. Jr,, Deerfield, D.W. II, 1997. GeneDoc: Analysis and Visualization of Genetic Variation. EMBNEW NEWS 4:14.
  14. Nilsson, L. O., Edalat, M., Pettersson, P. L., Mannervik, B., 2002. Aromatic residues in the C-terminal region of glutathione transferase A1-1 influence ratedetermining steps in the catalytic mechanism. Biochimica et Biophysica Acta 29: 1598(1-2):199- 205.
  15. Perbandt, M., Burmeister, C., Walter, R. D., Betzel, C., Liebau, E., 2004. Native and inhibited structure of a Mu class-related glutathione S-transferase from Plasmodium falciparum. J. Biol. Chem. 279, 1336- 1342.
  16. Rambaut, A., 2006. FigTree: Tree figure drawing tool, version 1.0. Available from, Institute of Evolutionary Biology, University of Edinburgh.
  17. Ricci, G., De Maria, F., Antonini, G., Turella, P., Bullo, A., Stella, L., Filomeni, G., Federici, G., Caccuri, A.M. 2005. 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione Stransferases. The Journal of Biological Chemistry 280:28, 26397-26405.
  18. Roberts, E., Eargle, J., Wright, D., Luthey-Schulten, Z., 2006. MultiSeq: unifying sequence and structure data for evolutionary analysis. BMC Bioinformatics. Aug 16;7:382.
  19. Rusell, S., 2004. The economic burden of illness for households in developing countries: a review of studies focusing on malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome. Am J Trop Med Hyg.71 (2 Suppl):147-55.
  20. Srivastava, P., Puri, S.K., Kamboj, K.K., and Pandey, V.C. 1999. Glutathione S-transferase activity in malarial parasites. Trop. Med. Int. Health 4:251-254.
  21. Tamura, K., Dudley, J., Nei, M., Kumar, S., 2007. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Molecular Biology and Evolution 24: 1596-1599.
  22. Torres-Rivera, A., Landa, A., 2008. Glutathione transferases from parasites: A biochemical view. Acta Tropica 105: 99-112.
  23. Vega-Rodríguez, J., Franke-Fayard, B., Dinglasan, R.R., Janse, C.J., Pastrana-Mena, R., Waters, A.P., Coppens, I., Rodríguez-Orengo, J.F., Jacobs-Lorena, M., Serrano, A.E. 2009. The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission. PLoS Pathogens 5:2.
  24. Winayanuwattikun, P., Ketterman, A.J., 2005. An electron-sharing network involved in the catalytic mechanism is functionally conserved in different glutathione transferase classes. The Journal of Biological Chemistry.
  25. Whitty, C.J., Rowland, M., Sanderson, F., Mutabingwa, T.K., 2002. Science, medicicne, and the future: Malaria. BMJ 325(7374):1221-1224.
  26. WHO, 2005. Global malaria situation. http://www.who. int/globalatlas/autologin/malria_login.asp
  27. Wongsrichanalai, C., Pickard, A.L., Wernsdorfer, W.H., Meshnick, S.R. 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 4:209-18.
  28. Wu, C.H., Huang, H., Nikolskaya, A., Hu, Z., Barker, W.C., 2004. The iProClass integrated database for protein functional analysis. Comput Biol Chem. Feb;28(1):87-96.

Paper Citation

in Harvard Style

E. Colón-Lorenzo E., E. Serrano A., B. Nicholas Jr H., Wymore T., J. Ropelewski A. and González-Méndez R. (2010). THE PLASMODIUM GLUTATHIONE S-TRANSFERASE - Bioinformatics Characterization and Classification into the Sigma Class . In Proceedings of the First International Conference on Bioinformatics - Volume 1: BIOINFORMATICS, (BIOSTEC 2010) ISBN 978-989-674-019-1, pages 173-180. DOI: 10.5220/0002747401730180

in Bibtex Style

author={Emilee E. Colón-Lorenzo and Adelfa E. Serrano and Hugh B. Nicholas Jr and Troy Wymore and Alexander J. Ropelewski and Ricardo González-Méndez},
title={THE PLASMODIUM GLUTATHIONE S-TRANSFERASE - Bioinformatics Characterization and Classification into the Sigma Class},
booktitle={Proceedings of the First International Conference on Bioinformatics - Volume 1: BIOINFORMATICS, (BIOSTEC 2010)},

in EndNote Style

JO - Proceedings of the First International Conference on Bioinformatics - Volume 1: BIOINFORMATICS, (BIOSTEC 2010)
TI - THE PLASMODIUM GLUTATHIONE S-TRANSFERASE - Bioinformatics Characterization and Classification into the Sigma Class
SN - 978-989-674-019-1
AU - E. Colón-Lorenzo E.
AU - E. Serrano A.
AU - B. Nicholas Jr H.
AU - Wymore T.
AU - J. Ropelewski A.
AU - González-Méndez R.
PY - 2010
SP - 173
EP - 180
DO - 10.5220/0002747401730180