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Computational Study of Mycobacterium smegmatis Acyl Transferase Reaction Mechanism and Specificity
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0002-6542-6649
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0002-1012-5611
Number of Authors: 42018 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 8, no 11, p. 10698-10706Article in journal (Refereed) Published
Abstract [en]

The acyl transferase from Mycobacterium smegmatis (MsAcT) catalyzes the acyl transfer between a range of primary and secondary alcohols, whereby its outstanding ability is to perform this reaction in aqueous solution. Therefore, MsAcT opens different options for acylation reactions enabling alternatives for many conventionally hydrolytic enzymes used in biocatalysis. Nevertheless, hydrolysis is still a major side reaction of this enzyme. To provide a detailed understanding of the competition between hydrolysis and transesterification reactions, a combination of density functional theory and free energy perturbation methods have been employed. The relative binding free energies and the energy profiles of the chemical steps involved in the reaction were calculated for a number of substrates. The calculations show that the enzyme active site exhibits a higher affinity for substrates with an aromatic ring. The rate-determining step corresponds to the collapse of a negatively charged tetrahedral intermediate in the substrate acylation half-reaction. The intrinsic barriers of the transesterification and hydrolysis half-reactions are calculated to be of similar heights, suggesting that the determining factor in the MsAcT specificity is the higher binding affinity of the active site for the alcohol substrates relative to water. Finally, the influence of the acyl donor on the MsAcT-catalyzed reaction is also investigated by considering different esters in the calculations.

Place, publisher, year, edition, pages
2018. Vol. 8, no 11, p. 10698-10706
Keywords [en]
acylation, transesterification, enzymology, density functional theory, free energy perturbation, transition state, reaction mechanism
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-162978DOI: 10.1021/acscatal.8b03360ISI: 000449723900084OAI: oai:DiVA.org:su-162978DiVA, id: diva2:1271220
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-12-17Bibliographically approved

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Kazemi, MasoudSheng, XiangKroutil, WolfgangHimo, Fahmi
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