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An Esterase‐like Lyase Catalyzes Acetate Elimination in Spirotetronate/Spirotetramate Biosynthesis

Lookup NU author(s): Dr Polly Moreland, Dr James StachORCiD, Professor Paul RaceORCiD



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.

Publication metadata

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

Year: 2019

Volume: 58

Issue: 8

Pages: 2305-2309

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

Publisher: Wiley


DOI: 10.1002/anie.201812105


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