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An esterase‐like lyase catalyzes acetate elimination in spirotetronate/spirotetramate biosynthesis

DOI: 10.1002/anie.201812105 DOI Help

Authors: Nicholas R. Lees (University of Bristol) , Li-chen Han (University of Bristol) , Matthew J. Byrne (University of Bristol) , Jonathan Davies (University of Bristol) , Alice E. Parnell (University of Bristol) , Pollyanna E. Moreland (Newcastle University) , James E. M. Stach (Newcastle University) , Marc W. Van Der Kamp (University of Bristol) , Christine L. Willis (University of Bristol) , Paul R. Race (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: January 2019

Abstract: 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 acetate elimination catalyzed by AbyA5, implicated in the formation of the key Diels–Alder substrate to give the spirocyclic system of the antibiotic abyssomicin C. Using synthetic substrate analogues, it is shown 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 show the use of a His‐Ser dyad to catalyze either elimination or hydrolysis, via disparate mechanisms, under substrate control.

Journal Keywords: antibiotics; biocatalysis; enzyme structure; enzymology; polyketides

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography