An Evolutionary Model Encompassing Substrate Specificity and Reactivity of Type I Polyketide Synthase Thioesterases

Bacterial polyketides are a rich source of chemical diversity and pharmaceutical agents. Understanding the biochemical basis for their biosynthesis and the evolutionary driving force leading to this diversity is essential to take advantage of the enzymes as biocatalysts and to access new chemical di...

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Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2014-12, Vol.15 (18), p.2656-2661
Main Authors: Hari, Taylor P. A., Labana, Puneet, Boileau, Meaghan, Boddy, Christopher N.
Format: Article
Language:English
Subjects:
Bacteria - enzymology
Bacteria - genetics
Evolution, Molecular
macrodiolide
macrolactone
Macrolides - chemistry
Macrolides - metabolism
Phylogeny
Polyketide Synthases - genetics
Polyketide Synthases - metabolism
screening hypothesis
substrate selectivity
Substrate Specificity
thioesterase
Thiolester Hydrolases - genetics
Thiolester Hydrolases - metabolism
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Summary:Bacterial polyketides are a rich source of chemical diversity and pharmaceutical agents. Understanding the biochemical basis for their biosynthesis and the evolutionary driving force leading to this diversity is essential to take advantage of the enzymes as biocatalysts and to access new chemical diversity for drug discovery. Biochemical characterization of the thioesterase (TE) responsible for 6‐deoxyerythronolide macrocyclization shows that a small, evolutionarily accessible change to the substrate can increase the chemical diversity of products, including macrodiolide formation. We propose an evolutionary model in which TEs are by nature non‐selective for the type of chemistry they catalyze, producing a range of metabolites. As one metabolite becomes essential for improving fitness in a particular environment, the TE evolves to enrich for that corresponding reactivity. This hypothesis is supported by our phylogenetic analysis, showing convergent evolution of macrodiolide‐forming TEs. Evolution of diolide formation: We propose an evolutionary model in which thioesterases from polyketide biosynthesis are by nature non‐selective for the type of chemistry they catalyze, producing a range of metabolites including acids, macrolactones, dimers, and macrodiolides. As one metabolite becomes essential for improving fitness in a particular environment, the thioesterase evolves to enrich for that corresponding reactivity.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201402475