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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Royal Society of Chemistry.The Diels-Alder reaction is one of the most effective methods for the synthesis of substituted cyclohexenes. The development of protein catalysts for this reaction remains a major priority, affording new sustainable routes to high value target molecules. Whilst a small number of natural enzymes have been shown capable of catalysing [4 + 2] cycloadditions, there is a need for significant mechanistic understanding of how these prospective Diels-Alderases promote catalysis to underpin their development as biocatalysts for use in synthesis. Here we present a molecular description of the complete reaction cycle of the bona fide natural Diels-Alderase AbyU, which catalyses formation of the spirotetronate skeleton of the antibiotic abyssomicin C. This description is derived from X-ray crystallographic studies of AbyU in complex with a non-transformable synthetic substrate analogue, together with transient kinetic analyses of the AbyU catalysed reaction and computational reaction simulations. These studies reveal the mechanistic intricacies of this enzyme system and establish a foundation for the informed reengineering of AbyU and related biocatalysts.
Author(s): Maschio L, Back CR, Alnawah J, Bowen JI, Johns ST, Mbatha SZ, Han L-C, Lees NR, Zorn K, Stach JEM, Hayes MA, van der Kamp MW, Pudney CR, Burston SG, Willis CL, Race PR
Publication type: Article
Publication status: Published
Journal: Chemical Science
Year: 2024
Pages: epub ahead of print
Online publication date: 24/06/2024
Acceptance date: 19/06/2024
Date deposited: 23/07/2024
ISSN (print): 2041-6520
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/D4SC02908A
DOI: 10.1039/d4sc02908a
Data Access Statement: The data supporting this article have been included as part of the ESI
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