Lookup NU author(s): Dr Polly Moreland,
Dr James Stach
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Wiley, 2019.
For re-use rights please refer to the publisher's terms and conditions.
Spirotetronate and spirotetramate natural products include a multitude of compounds with potent antimicrobial and antitumor activities. Their biosynthesis incorporates many unusual biocatalytic steps, including regio- and stereo-specific modifications, cyclizations promoted by Diels-Alderases, and acetylation-elimination reactions. Here we focus on the intriguing acetate elimination catalyzed by AbyA5, implicated in formation of the key Diels-Alder substrate to give the spirocyclic system of the antibiotic abyssomicin C. Using synthetic substrate analogues we show that AbyA5 catalyzes stereospecific acetate elimination, establishing the (R)-tetronate acetate as a biosynthetic intermediate. The X-ray crystal structure of AbyA5, the first of an acetate eliminating enzyme, reveals a deviant acetyl esterase fold. Molecular dynamics simulations and enzyme assays demonstrate use of a His-Ser dyad to catalyze either elimination or hydrolysis, via disparate mechanisms, under substrate control.
Author(s): Lees NR, Han LC, Byrne MJ, Davies JA, Parnell AE, Moreland PEJ, Stach JEM, van der Kamp MW, Willis CL, Race PR
Publication type: Article
Publication status: Published
Journal: Angewandte Chemie International Edition
Print publication date: 11/02/2019
Online publication date: 21/01/2019
Acceptance date: 20/12/2018
Date deposited: 07/01/2019
ISSN (print): 0044-8249
ISSN (electronic): 1521-3757
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