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Insights Into the Enzymatic Mechanism of 6-Phosphogluconolactonase from Trypanosoma brucei Using Structural Data and Molecular Dynamics Simulation |
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| Authors: | Nathalie Duclert-Savatier,Emeric Miclet,Jamal Ouazzani,Michael Nilges,Vé ronique Stoven |
| Affiliation: | 1 Unité de Bioinformatique Structurale, Institut Pasteur, URA 2185 du CNRS, 25 rue du Docteur Roux, 75015 Paris, France 2 Unité de Dynamique Structurale des Macromolecules, Institut Pasteur, URA 2185 du CNRS, 25 rue du Docteur Roux, 75015 Paris, France 3 Université Pierre et Marie Curie-Paris 6, UMR 7613 du CNRS, Paris, France; UMR 7613 du CNRS, Paris, France; FR 2769, UMR 7613, Paris, France; Case courier 45, 4 place Jussieu, 75005 Paris, France 4 Institut de Chimie des Substances Naturelles, UPR 2301 du CNRS, avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France 5 Research Unit for Tropical Diseases, de Duve Institute, and Laboratory of Biochemistry, Université catholique de Louvain, Brussels, Belgium 6 Mines ParisTech, Centre for Computational Biology, 35 rue Saint Honoré, Fontainebleau F-77300 France; Institut Curie, France; INSERM, U900, Paris, France |
| Abstract: | Trypanosoma brucei is the causative agent of African sleeping sickness. Current work for the development of new drugs against this pathology includes evaluation of enzymes of the pentose phosphate pathway (PPP), which first requires a clear understanding of their function and mechanism of action. In this context, we focused on T. brucei 6-phosphogluconolactonase (Tb6PGL), which converts δ-6-phosphogluconolactone into 6-phosphogluconic acid in the second step of the PPP. We have determined the crystal structure of Tb6PGL in complex with two ligands, 6-phosphogluconic acid and citrate, at 2.2 Å and 2.0 Å resolution, respectively. We have performed molecular dynamics (MD) simulations on Tb6PGL in its empty form and in complex with δ-6-phosphogluconolactone, its natural ligand. Analysis of the structural data and MD simulations allowed us to propose a detailed enzymatic mechanism for 6PGL enzymes. |
| Keywords: | PPP, pentose phosphate pathway Tb, Trypanosoma brucei 6PGL, 6-phosphogluconolactonase 6PGA, 6-phosphogluconic acid PDB, protein data bank MD, molecular dynamics AGP, 2-deoxy-2-amino glucitol 6-phosphate F6R, fructose 6-phosphate |
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