ArticleJournal of the American Chemical Society2025
Establishing Selectivity Trends with Reactions of Thioesterases and Semi-Synthetic Polyketides.
Article in Journal of the American Chemical Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Polyketides are a diverse class of natural products with a wide range of therapeutic properties. They have been widely used in clinical settings as antibiotics, antifungals, anticancer agents, and immunosuppressants. A major subset of these molecules is produced by type I assembly line polyketide synthases (T1ALPKSs), large enzyme complexes that catalyze their stepwise construction. Understanding the selectivity and scope of T1ALPKS domains could greatly expand the diversity of products generated by these synthases and their components. This study explores the reactivity and selectivity of the terminal domains of T1ALPKSs, known as thioesterases (TEs). A panel of 25 wild-type and 10 mutant (Ser→Cys) thioesterases was reacted with semisynthetic substrates. The selectivity with which these TEs form 12- and/or 14-membered macrolactones and one or both of a pair of diastereomeric 14-membered macrolactones was quantified. The results indicate that the selectivity with which wild-type TEs react with unnatural substrates correlates with their parent T1ALPKSs, enabling the assignment of TEs into groups. Additionally, our experiments reveal that mutant (Ser→Cys) TEs often have expanded scopes compared to their wild-type counterparts and that some wild-type TEs are capable of hydrolyzing macrolactones. We demonstrated the synthetic applications of TEs with kinetic resolutions and preparative-scale reactions. This study provides a framework for organizing TEs and predicting their reactivity and selectivity, facilitating future research on structure-activity relationships and supporting directed evolution studies.
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