[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content
Springer Nature Link
Log in

Structure Prediction and Docking Studies of Chorismate Synthase from Mycobacterium Tuberculosis

  • Conference paper
Advances in Bioinformatics and Computational Biology (BSB 2005)

Part of the book series: Lecture Notes in Computer Science ((LNBI,volume 3594))

Included in the following conference series:

Abstract

The enzymes of the shikimate pathway constitute an excellent target for the design of new antibacterial agents. This pathway is found in bacteria, fungi, plants and apicomplexan parasites but is absent in mammals. Chorismate Synthase (CS) catalyzes the last step of this pathway, the product of which is utilized in other enzymatic transformations like the biosynthesis of aromatic amino acids, folate, vitamin K and ubiquinone. This reaction is the most unusual of the entire pathway and is unique in nature. It converts EPSP to chorismate in the presence of a reduced FMN cofactor. Structure prediction used the comparative protein structure modeling methodology. The three-dimensional (3D) structure prediction of the enzyme was performed using the crystal structure (PDB ID: 1QX0) of CS from Streptococcus pneumoniae as template (≈42% identity), and the MODELLER6v2 package. Additionally, in order to understand the possible binding modes of substrate and cofactor to the enzyme EPSP and FMN, respectively, were geometrically docked to CS. FMN binding to CS of M. tuberculosis (MTB) is similar to that of the S. pneumoniae template despite the change of Asn251 in S. pneumoniae to Gln256 in MTB. The longer side chain of Gln256 is overlapping with the FMN cofactor and a small conformational change is needed in order to properly accommodate this interaction. EPSP binding mode is also very similar to that of the template with three hydrogen bonds missing. This could be due to artifacts from the simple geometric docking we performed. Refinement with energy-based docking algorithms should relax the enzyme and substrates, thus promoting the expected interactions between them. Understanding the structure of MTB CS together with its cofactor and substrate binding modes should facilitate the search for inhibitors of this enzyme as alternative agents to treat tuberculosis.

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

Access this chapter

Log in via an institution

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Ahn, H.J., Yoon, H.-J., Lee II, B., Suh, S.W.: Crystal Structure of Chorismate Synthase: A novel FMN-binding Protein Fold and Funcional Insights. Journal of Molecular Biology 336, 903–915 (2004)

    Article  Google Scholar 

  2. Altschul, S.F., Madden, T.L., Schäffer, A.A., Zhang, J., Zhang, Z., Miller, W., Lipman, D.J.: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997)

    Article  Google Scholar 

  3. Bentley, R.: The Shikimate Pathway - A metabolic Tree with Many Branches. Critical Reviews in Biochemistry and Molecular Biology 25(5), 307–384 (1990)

    Article  Google Scholar 

  4. Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E.: The protein data bank. Nucleic Acids Research 28, 235–242 (2000)

    Article  Google Scholar 

  5. Bornemann, S., Lowe, D.J., Thorneley, R.N.F.: The Transient Kinetics of Escherichia coli Chorismate Synthase: Substrate Consuption, Product Formation, Phosphate Dissociation, and Characterization of a Flavin Intermediate. Biochemistry 35(30), 9907–9916 (1996)

    Article  Google Scholar 

  6. Cole, S.T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S.V., Eiglmeier, K., Gas, S., Barry, C.E., Tekaia, F., Badcock, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Feltwell, T., Gentles, S., Hamlin, N., Holroyd, S., Hornsby, T., Jagels, K., Krogh, A., McLean, J., Moule, S., Murphy, L., Oliver, K., Osborne, J., Quail, M.A., Rajandream, M.-A., Rogers, J., Rutter, S., Seeger, K., Skelton, J., Squares, R., Squares, S., Sulston, J.E., Taylor, K., Whitehead, S., Barrell, B.G.: Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998)

    Article  Google Scholar 

  7. Guex, N., Peitsch, M.C.: SWISS-MODEL and The Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997)

    Article  Google Scholar 

  8. Kitzing, K., Auweter, S., Amrhein, N., Macheroux, P.: Mechanism of Chorismate Synthase: Role of the Two Invariant Histidine Residues in the Active Site - In Press. Journal of Biological Chemistry (December 10, 2003)

    Google Scholar 

  9. Laskowski, R.A., MacArthur, M.W., Moss, D.S., Thornton, J.M.: PROCHECK: a program to check the stereochemical quality of protein structures. Journal of Appl. Cryst. 26, 283–291 (1993)

    Article  Google Scholar 

  10. Lüthy, R., Bowie, J.U., Eisenberg, D.: Assessment of protein models with three-dimensional profiles. Nature 356, 83–85 (1992)

    Article  Google Scholar 

  11. Macheroux, P., Bornemann, S., Ghisla, S., Thrneley, R.N.F.: Studies with Flavin Analogs Provide Evidence That a Protonated Reduced FMN is the Substrate-induced Transient Intermediate in the Reaction of Escherichia coli Chorismate Synthase. The Journal of Biological Chemistry 271(42), 25850–25858 (1996)

    Article  Google Scholar 

  12. Macheroux, P., Schmid, J., Amrhein, N., Schaller, A.: A Unique reaction in a Common Pathway: Mechanism and Function of Chorismate Synthase in the Shikimate Pathway. Planta 207, 325–334 (1999)

    Article  Google Scholar 

  13. MaClean, J., Ali, S.: The Structure of Chorismate Synthase Reveals a Novel Flavin Binding Site Fundamental to a Unique Chemical reaction. Structure 11, 1499–1511 (2003)

    Article  Google Scholar 

  14. Martí-Renom, M.A., Stuart, A.C., Fiser, A., Sánchez, R., Melo, F., Šali, A.: Comparative Protein Structure Modeling of Genes and Genomes. Annual Reviews Biophis. Biomol. Structure 29, 291–325 (2000)

    Article  Google Scholar 

  15. Quevillon-Cheruel, S., Leulliot, N., Meyer, P., Graille, M., Bremang, M., Blondeau, K., Sorel, I., Poupon, A., van Tilbeurgh, J.n.H.: Crystal Structure of the Bifunctional Chorismate Synthase from Saccharomyces cerevisiae. The Journal of Biological Chemistry 279(1), 619–625 (2004)

    Article  Google Scholar 

  16. Roberts, F., Roberts, C.W., Johnson, J.J., Kyle, D.E., Krell, T., Coggins, J., Coombs, G.H., Milhous, W.K., Tzipori, S., Ferguson, D.J.P., Chakrabarti, D., McLeod, R.: Evidence for the Shikimate pathway in Apicomplexan Parasites. Nature 393, 801–805 (1998)

    Article  Google Scholar 

  17. Sigrist, C.J.A., Cerutti, L., Hulo, N., Gattiker, A., Falquet, L., Pagni, M., Bairoch, A., Bucher, P.: PROSITE: a documented database using patterns and profiles as motif descriptors. Bioinform. 3, 265–274 (2002)

    Google Scholar 

  18. Thompson, J.D., Higgins, D.G., Gibson, T.J.: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Research 22(22), 4673–4680 (1994)

    Article  Google Scholar 

  19. Šali, A., Blundell, T.L.: Comparative Protein Modelling by Satisfaction of Spatial Restraints. Journal of Molecular Biology 234(3), 779–815 (1993)

    Article  Google Scholar 

  20. Wallace, A.C., Laskowski, R.A., Thornton, J.M.: LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Engineering Design and Seletion 8, 127–134 (1995)

    Article  Google Scholar 

  21. World Health Organization, USA. Global Tuberculosis Control Report 2004 (2004), http://www.who.int/tb/en

Download references

Author information

Authors and Affiliations

  1. Laboratório de Bioinformática, Modelagem e Simulação de Biossistemas – LABIO, Pontifícia Universidade Católica do Rio Grande do Sul,  

    Cláudia Lemelle Fernandes & Osmar Norberto de Souza

  2. Centro de Pesquisa em Biologia Molecular e Funcional, TECNOPUC, PUCRS,  

    Diógenes Santiago Santos, Luiz Augusto Basso & Osmar Norberto de Souza

  3. Instituto de Pesquisas Biomédicas, PUCRS,  

    Diógenes Santiago Santos & Osmar Norberto de Souza

  4. Dep. de Biologia Molecular e Biotecnologia, UFRGS, Porto Alegre, RS, Brasil

    Luiz Augusto Basso

Authors
  1. Cláudia Lemelle Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diógenes Santiago Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luiz Augusto Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Osmar Norberto de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Computer Science, Virginia Bioinformatics Institute and Virginia Polytechnic Institute and State University, Bioinformatics 1, Box 0477, 24060-0477, Blacksburg, VA, USA

    João Carlos Setubal

  2. Instituto de Quimica, Departamento de Bioquimica, Universidade de Sao Paulo, Av. Prof. Lineu Prestes 748, 05508-000, Sao Paulo, SP, Brazil

    Sergio Verjovski-Almeida

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Fernandes, C.L., Santos, D.S., Basso, L.A., de Souza, O.N. (2005). Structure Prediction and Docking Studies of Chorismate Synthase from Mycobacterium Tuberculosis . In: Setubal, J.C., Verjovski-Almeida, S. (eds) Advances in Bioinformatics and Computational Biology. BSB 2005. Lecture Notes in Computer Science(), vol 3594. Springer, Berlin, Heidelberg. https://doi.org/10.1007/11532323_13

Download citation

  • DOI: https://doi.org/10.1007/11532323_13

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-28008-8

  • Online ISBN: 978-3-540-31861-3

  • eBook Packages: Computer ScienceComputer Science (R0)

Publish with us

Policies and ethics

Search

Navigation