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Molecular mechanism of a hotdog-fold acyl-CoA thioesterase.

Chemistry. 2014 Jul 14;20(29):9045-51. doi:10.1002/chem.201304228. Epub 2014 Jun 04
David C Cantu 1 , Albert Ardèvol , Carme Rovira , Peter J Reilly
David C Cantu 1 , Albert Ardèvol , Carme Rovira , Peter J Reilly

[No authors listed]

Author information
  • 1 Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa 50011-2230 (USA).

摘要


Thioesterases are enzymes that hydrolyze thioester bonds between a carbonyl group and a sulfur atom. They catalyze key steps in fatty acid biosynthesis and metabolism, as well as polyketide biosynthesis. The reaction molecular mechanism of most hotdog-fold acyl-CoA thioesterases remains unknown, but several hypotheses have been put forward in structural and biochemical investigations. The reaction of a human thioesterase (hTHEM2), representing a thioesterase family with a hotdog fold where a coenzyme A moiety is cleaved, was simulated by quantum mechanics/molecular mechanics metadynamics techniques to elucidate atomic and electronic details of its mechanism, its transition-state conformation, and the free energy landscape of the process. A single-displacement acid-base-like mechanism, in which a nucleophilic water molecule is activated by an aspartate residue acting as a base, was found, confirming previous experimental proposals. The results provide unambiguous evidence of the formation of a tetrahedral-like transition state. They also explain the roles of other conserved active-site residues during the reaction, especially that of a nearby histidine/serine pair that protonates the thioester sulfur atom, the participation of which could not be elucidated from mutation analyses alone.

KEYWORDS: Car-Parrinello, metadynamics, molecular dynamics, nucleophilic attack, protonation

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