Understanding the different activities of highly promiscuous MbtI by computational methods

Literature Information

Publication Date 2012-01-17
DOI 10.1039/C2CP23149B
Impact Factor 3.676
Authors

Silvia Ferrer, Sergio Martí, Vicent Moliner, Iñaki Tuñón, Juan Bertrán


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Abstract

Salicylate synthase from Mycobacterium tuberculosis, MbtI, is a highly promiscuous Mg2+ 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. Mg2+ would be polarizing and pre-organizing the substrate and active site, as well as shifting the pKa values of key active site residues.

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Physical Chemistry Chemical Physics

Physical Chemistry Chemical Physics
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