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  Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition

Zheng, Y., & Thiel, W. (2017). Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition. Journal of Organic Chemistry, 82(24), 13563-13571. doi:10.1021/acs.joc.7b02794.

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 Creators:
Zheng, Yiying1, Author              
Thiel, Walter1, Author              
Affiliations:
1Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445590              

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 Abstract: The enzyme SpnF, involved in the biosynthesis of spinosyn A, catalyzes a formal [4+2] cycloaddition of a 22-membered macrolactone, which may proceed as a concerted [4+2] Diels–Alder reaction or a stepwise [6+4] cycloaddition followed by a Cope rearrangement. Quantum mechanics/molecular mechanics (QM/MM) calculations combined with free energy simulations show that the Diels–Alder pathway is favored in the enzyme environment. OM2/CHARMM free energy simulations for the SpnF-catalyzed reaction predict a free energy barrier of 22 kcal/mol for the concerted Diels–Alder process and provide no evidence of a competitive stepwise pathway. Compared with the gas phase, the enzyme lowers the Diels–Alder barrier significantly, consistent with experimental observations. Inspection of the optimized geometries indicates that the enzyme may prearrange the substrate within the active site to accelerate the [4+2] cycloaddition and impede the [6+4] cycloaddition through interactions with active-site residues. Judging from partial charge analysis, we find that the hydrogen bond between the Thr196 residue of SpnF and the substrate C15 carbonyl group contributes to the enhancement of the rate of the Diels–Alder reaction. QM/MM simulations show that the substrate can easily adopt a reactive conformation in the active site of SpnF because interconversion between the C5–C6 s-trans and s-cis conformers is facile. Our QM/MM study suggests that the enzyme SpnF does behave as a Diels-Alderase.

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Language(s): eng - English
 Dates: 2017-11-042017-11-132017-12-15
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acs.joc.7b02794
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Title: Journal of Organic Chemistry
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: - Volume / Issue: 82 (24) Sequence Number: - Start / End Page: 13563 - 13571 Identifier: ISSN: 0022-3263
CoNE: https://pure.mpg.de/cone/journals/resource/954925416967