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

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dc.contributor.authorMarques, Maurício Ribeiro [UNESP]
dc.contributor.authorPereira, José Henrique [UNESP]
dc.contributor.authorOliveira, Jaim S.
dc.contributor.authorBasso, Luiz Augusto
dc.contributor.authorde Azevedo Jr., Walter Filgueira
dc.contributor.authorSantos, Diógenes Santiago
dc.contributor.authorPalma, Mario Sergio [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniversidade Federal do Rio Grande do Sul (UFRGS)
dc.contributor.institutionPontifícia Universidade Católica do Rio Grande do Sul (PUCRS)
dc.date.accessioned2014-05-27T11:22:25Z
dc.date.available2014-05-27T11:22:25Z
dc.date.issued2007-03-01
dc.description.abstractEPSP 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 βαβαββ-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. © 2007 Bentham Science Publishers Ltd.en
dc.description.affiliationLaboratory of Structural Biology and Zoochemistry CEIS/Department of Biology UNESP, Rio Claro, SP 13506-900
dc.description.affiliationPrograma de Pós-Graduação em Biofísica Molecular Departamento de Física UNESP, Sao Jose do Rio Preto, SP 15054-000
dc.description.affiliationRede Brasileira de Pesquisas em Tuberculose Grupo de Microbiologia Molecular e Funcional Centro de Biotecnologia UFRGS, Porto Alegre, RS 91501-970
dc.description.affiliationCentro de Pesquisas em Biologia Molecular e Funcional PUCRS, Avenida Ipiranga 6681, 90619-900 Porto Alegre, RS
dc.description.affiliationFaculdade de Biociências PUCRS, Porto Alegre, RS
dc.description.affiliationUnespLaboratory of Structural Biology and Zoochemistry CEIS/Department of Biology UNESP, Rio Claro, SP 13506-900
dc.description.affiliationUnespPrograma de Pós-Graduação em Biofísica Molecular Departamento de Física UNESP, Sao Jose do Rio Preto, SP 15054-000
dc.format.extent445-457
dc.identifierhttp://dx.doi.org/10.2174/138945007780058951
dc.identifier.citationCurrent Drug Targets, v. 8, n. 3, p. 445-457, 2007.
dc.identifier.doi10.2174/138945007780058951
dc.identifier.issn1389-4501
dc.identifier.lattes2901888624506535
dc.identifier.scopus2-s2.0-33847694649
dc.identifier.urihttp://hdl.handle.net/11449/69563
dc.identifier.wosWOS:000244702900007
dc.language.isoeng
dc.relation.ispartofCurrent Drug Targets
dc.relation.ispartofjcr3.112
dc.relation.ispartofsjr0,906
dc.rights.accessRightsAcesso restrito
dc.sourceScopus
dc.subjectActive site
dc.subjectDomain
dc.subjectEnzyme catalysis
dc.subjectEnzyme kinetics
dc.subjectEPSP synthase
dc.subjectGlyphosate
dc.subjectInhibitor
dc.subjectStructural determination
dc.subject3 phosphoshikimate 1 carboxyvinyltransferase
dc.subject3 phosphoshikimate 1 carboxyvinyltransferase inhibitor
dc.subjectantifungal agent
dc.subjectantiinfective agent
dc.subjectantiparasitic agent
dc.subjectfosfomycin
dc.subjectglyphosate
dc.subjectshikimic acid
dc.subjectunclassified drug
dc.subjectamino terminal sequence
dc.subjectbacterial gene
dc.subjectbacterial strain
dc.subjectcarboxy terminal sequence
dc.subjectcatalysis
dc.subjectdrug design
dc.subjectdrug mechanism
dc.subjectdrug research
dc.subjectdrug structure
dc.subjectdrug synthesis
dc.subjectdrug targeting
dc.subjectenzyme active site
dc.subjectenzyme activity
dc.subjectenzyme analysis
dc.subjectenzyme binding
dc.subjectenzyme inhibition
dc.subjectenzyme mechanism
dc.subjectenzyme modification
dc.subjectenzyme structure
dc.subjectgene structure
dc.subjectgenetic code
dc.subjecthuman
dc.subjectminimum inhibitory concentration
dc.subjectmolecular docking
dc.subjectnonhuman
dc.subjectopportunistic infection
dc.subjectparasitosis
dc.subjectprotein domain
dc.subjectprotein targeting
dc.subjectreview
dc.subjectsite directed mutagenesis
dc.subjectstructure activity relation
dc.subjectstructure analysis
dc.subject3-Phosphoshikimate 1-Carboxyvinyltransferase
dc.subjectAnimals
dc.subjectAnti-Infective Agents
dc.subjectDrugs, Investigational
dc.subjectEnzyme Inhibitors
dc.subjectHumans
dc.subjectModels, Chemical
dc.titleThe inhibition of 5-enolpyruvylshikimate-3-phosphate synthase as a model for development of novel antimicrobialsen
dc.typeResenha
dcterms.licensehttp://eurekaselect.com/209
unesp.author.lattes2901888624506535
unesp.author.orcid0000-0002-7363-8211[7]
unesp.author.orcid0000-0003-4971-463X[6]
unesp.author.orcid0000-0003-0903-2407[4]
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências, Rio Claropt
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências Letras e Ciências Exatas, São José do Rio Pretopt

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Artigos - Biologia - IBRC
Artigos - Física - IBILCE