title: The inhibition of 5-enolpyruvylshikimate-3-phosphate synthase as a model for development of novel antimicrobials.
abstract: EPSP synthase (EPSPS) is an essential enzyme in the shikimate pathway, transferring the enolpyruvyl group of phosphoenolpyruvate to shikimate-3-phosphate to form 5-enolpyruvyl-3-shikimate phosphate and inorganic phosphate. This enzyme is composed of two domains, which are formed by three copies of betaalphabetaalphabetabeta-folding units; in between there are two crossover chain segments hinging the nearly topologically symmetrical domains together and allowing conformational changes necessary for substrate conversion. The reaction is ordered with shikimate-3-phosphate binding first, followed by phosphoenolpyruvate, and then by the subsequent release of phosphate and EPSP. N-[phosphomethyl]glycine (glyphosate) is the commercial inhibitor of this enzyme. Apparently, the binding of shikimate-3-phosphate is necessary for glyphosate binding, since it induces the closure of the two domains to form the active site in the interdomain cleft. However, it is somehow controversial whether binding of shikimate-3-phosphate alone is enough to induce the complete conversion to the closed state. The phosphoenolpyruvate binding site seems to be located mainly on the C-terminal domain, while the binding site of shikimate-3-phosphate is located primarily in the N-terminal domain residues. However, recent results demonstrate that the active site of the enzyme undergoes structural changes upon inhibitor binding on a scale that cannot be predicted by conventional computational methods. Studies of molecular docking based on the interaction of known EPSPS structures with (R)- phosphonate TI analogue reveal that more experimental data on the structure and dynamics of various EPSPS-ligand complexes are needed to more effectively apply structure-based drug design of this enzyme in the future.
authors.affiliation: Laboratory of Structural Biology and Zoochemistry, CEIS/Department of Biology, Institute of Biosciences, São Paulo State University (UNESP), Rio Claro, SP, 13506-900, Brazil.
authors.forename: Maurício Ribeiro
authors.initials: MR
authors.lastname: Marques
authors.forename: José Henrique
authors.initials: JH
authors.lastname: Pereira
authors.forename: Jaim S
authors.initials: JS
authors.lastname: Oliveira
authors.forename: Luiz Augusto
authors.initials: LA
authors.lastname: Basso
authors.forename: Walter Filgueira
authors.initials: WF
authors.lastname: de Azevedo
authors.forename: Diógenes Santiago
authors.initials: DS
authors.lastname: Santos
authors.forename: Mário Sérgio
authors.initials: MS
authors.lastname: Palma
mesh_terms: D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015507:Drugs, Investigational / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical
chemical_list: D000890:Anti-Infective Agents; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase