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

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 a...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2019-02, Vol.58 (8), p.2305-2309
Main Authors: Lees, Nicholas R., Han, Li‐Chen, Byrne, Matthew J., Davies, Jonathan A., Parnell, Alice E., Moreland, Pollyanna E. J., Stach, James E. M., van der Kamp, Marc W., Willis, Christine L., Race, Paul R.
Format: Article
Language:English
Subjects:
Acetic acid
Acetylation
Antibiotics
Anticancer properties
biocatalysis
Biosynthesis
Chemical reactions
Crystal structure
enzyme structure
Enzymes
enzymology
Esterase
Molecular dynamics
Natural products
polyketides
Substrates
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. To eliminate, or to hydrolyze, that is the question: Structural, mechanistic, and computational studies of the abyssomicin C pathway enzyme AbyA5 establish the molecular origins of enzyme‐catalyzed acetate elimination. The unexpected acetyl‐esterase‐like scaffold of the protein is shown to support both acetate elimination and ester hydrolysis, in a manner dictated by substrate identity.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201812105