The inhibition of 5-enolpyruvylshikimate-3-phosphate synthase as a model for development of novel antimicrobials

Autor(es)

Ribeiro Marques‚ M. ; Henrique Pereira‚ J. ; Oliveira‚ J.S. ; Augusto Basso‚ L. ; Filgueira de Azevedo‚ W. ; Santiago Santos‚ D. ; Sergio Palma‚ M.

• Tipo de documento: Artigo Científico
• Fonte: CURRENT DRUG TARGETS; v. 8, n. 3, p. 445-457, 2007.

Resumo

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 B alpha B alpha BB-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. (AU)

• Processo FAPESP: 01/07532-0 - Structural genomics of cyclin dependent kinases and plant defensive proteinases and their natural inhibitors
• Beneficiário: Walter Filgueira de Azevedo Junior
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 03/12472-2 - Estudo estrutural de proteínas alvo de Mycobacterium tuberculosis
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 04/00217-0 - Estudo estrutural de proteinas alvos para desenho de drogas contra tuberculose.
• Beneficiário: Walter Filgueira de Azevedo Junior
• Modalidade de apoio: Auxílio à Pesquisa - Regular