Cláudia Lernelle FernandesDiógenes Santiago SantosLuiz Augusto BassoOsmar Norberto de Souza

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.

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