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Lookup NU author(s): Dr James StachORCiD, Professor Paul RaceORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Royal Society of Chemistry.The abyssomicins are a structurally intriguing family of bioactive natural products that include compounds with potent antibacterial, antitumour and antiviral activities. The biosynthesis of the characteristic abyssomicin spirotetronate core occurs via an enzyme-catalysed intramolecular Diels-Alder reaction, which proceeds via one of two distinct stereochemical pathways to generate products differing in configuration at the C15 spirocentre. Using the purified spirotetronate cyclases AbyU (from abyssomicin C/atrop-abyssomicin C biosynthesis) and AbmU (from abyssomicin 2/neoabyssomicin biosynthesis), in combination with synthetic substrate analogues, here we show that stereoselectivity in the spirotetronate-forming [4 + 2]-cycloaddition is controlled by a combination of factors attributable to both the enzyme and substrate. Furthermore, an achiral substrate was enzymatically cyclised to a single enantiomer of a spirocyclic product. X-ray crystal structures, molecular dynamics simulations, and assessment of substrate binding affinity and reactivity in both AbyU and AbmU establish the molecular determinants of stereochemical control in this important class of biocatalysts.
Author(s): Mbatha SZ, Back CR, Devine AJ, Mulliner HM, Johns ST, Lewin H, Cheung KA, Zorn K, Stach JEM, Hayes MA, van der Kamp MW, Race PR, Willis CL
Publication type: Article
Publication status: Published
Journal: Chemical Science
Year: 2024
Volume: 34
Issue: 15
Pages: 14009-14015
Online publication date: 12/08/2024
Acceptance date: 25/07/2024
Date deposited: 27/08/2024
ISSN (print): 2041-6520
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/d4sc03253e
DOI: 10.1039/d4sc03253e
Data Access Statement: The data supporting this article have been reported as part of the ESI. https://doi.org/10.1039/d4sc03253e
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