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RESEARCH PRODUCT
Understanding the different activities of highly promiscuous MbtI by computational methods
Iñaki TuñónSilvia FerrerSergio MartíVicent MolinerJuan Bertránsubject
Models MolecularPericyclic reactionbiologyATP synthaseStereochemistryChemistryGeneral Physics and AstronomyActive siteSubstrate (chemistry)LyasesMycobacterium tuberculosisHydrogen-Ion ConcentrationMolecular Dynamics SimulationLyaseMolecular mechanicsBiochemistryIsochorismate synthasebiology.proteinChorismate mutaseBiocatalysisQuantum TheoryMagnesiumPhysical and Theoretical Chemistrydescription
Salicylate synthase from Mycobacterium tuberculosis, MbtI, is a highly promiscuous Mg(2+) dependent enzyme with up to four distinct activities detected in vitro: isochorismate synthase (IS), isochorismate pyruvate lyase (IPL), salicylate synthase (SS) and chorismate mutase (CM). In this paper, Molecular Dynamic (MD) simulations employing hybrid quantum mechanics/molecular mechanics (QM/MM) potentials have been carried out to get a detailed knowledge of the IS and the IPL activities at the molecular level. According to our simulations, the architecture of the MbtI active site allows catalyzing the two reactions: the isochorismate formation, by means of a stepwise mechanism, and the salicylate production from isochorismate, that appears to be pericyclic in nature. Findings also explain the role of the magnesium cation and the pH dependence activity experimentally observed in MbtI. Mg(2+) would be polarizing and pre-organizing the substrate and active site, as well as shifting the pK(a) values of key active site residues.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-02-07 |