ArticleJournal of the American Chemical Society2013
Thioesterase domains of fungal nonreducing polyketide synthases act as decision gates during combinatorial biosynthesis.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 57 citations in OpenAlex.
- Resorcylic Acid Lactones and Isocoumarin Derivatives from the Marine-Associated Polar FungusMarine drugs · 2026Article
- A hybrid assembly mechanism employs nonreducing polyketide synthase-like logic for partially reduced polyketide formation.Marine life science & technology · 2026Article
- Decoding Pecan's Fungal Foe: A Genomic Insight intoJournal of fungi (Basel, Switzerland) · 2025Article
- Combinatorial biosynthesis for the engineering of novel fungal natural products.Communications chemistry · 2024Review
- Biosynthesis of Cytosporones in Leotiomycetous Filamentous Fungi.Journal of the American Chemical Society · 2024Article
- Putative Biosynthesis of Talarodioxadione & Talarooxime fromMolecules (Basel, Switzerland) · 2022Article
- Cloning and Functional Characterization of the Polyketide Synthases Based on Genome Mining ofFrontiers in microbiology · 2022Article
- Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from Fusarium graminearum PH-1.mSphere · 2020Article
- Intrinsic and Extrinsic Programming of Product Chain Length and Release Mode in Fungal Collaborating Iterative Polyketide Synthases.Journal of the American Chemical Society · 2020Article
- Probing Selectivity and Creating Structural Diversity Through Hybrid Polyketide Synthases.Angewandte Chemie (International ed. in English) · 2020Article
- Article
- Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds.Journal of the American Chemical Society · 2019Article
- Methylglucosylation of aromatic amino and phenolic moieties of drug-like biosynthons by combinatorial biosynthesis.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Analysis of the Sequences, Structures, and Functions of Product-Releasing Enzyme Domains in Fungal Polyketide Synthases.Frontiers in microbiology · 2017Article
- Engineering of New Pneumocandin Side-Chain Analogues from Glarea lozoyensis by Mutasynthesis and Evaluation of Their Antifungal Activity.ACS chemical biology · 2016Article
- Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases.Fungal genetics and biology : FG & B · 2016Review
- Diversity-Oriented Combinatorial Biosynthesis of Hybrid Polyketide Scaffolds from Azaphilone and Benzenediol Lactone Biosynthons.Organic letters · 2016Article
- Macrodiolide Formation by the Thioesterase of a Modular Polyketide Synthase.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2015Article
- Macrodiolide formation by the thioesterase of a modular polyketide synthase.Angewandte Chemie (International ed. in English) · 2015Article
- Recent advances in combinatorial biosynthesis for drug discovery.Drug design, development and therapy · 2015Review
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6 authors at 4 institutions in 2 countries.
Funding
Abstract
A crucial step during the programmed biosynthesis of fungal polyketide natural products is the release of the final polyketide intermediate from the iterative polyketide synthases (iPKSs), most frequently by a thioesterase (TE) domain. Realization of combinatorial biosynthesis with iPKSs requires TE domains that can accept altered polyketide intermediates generated by hybrid synthase enzymes and successfully release "unnatural products" with the desired structure. Achieving precise control over product release is of paramount importance with O-C bond-forming TE domains capable of macrocyclization, hydrolysis, transesterification, and pyrone formation that channel reactive, pluripotent polyketide intermediates to defined structural classes of bioactive secondary metabolites. By exploiting chimeric iPKS enzymes to offer substrates with controlled structural variety to two orthologous O-C bond-forming TE domains in situ, we show that these enzymes act as nonequivalent decision gates, determining context-dependent release mechanisms and overall product flux. Inappropriate choice of a TE could eradicate product formation in an otherwise highly productive chassis. Conversely, a judicious choice of a TE may allow the production of a desired hybrid metabolite. Finally, a serendipitous choice of a TE may reveal the unexpected productivity of some chassis. The ultimate decision gating role of TE domains influences the observable outcome of combinatorial domain swaps, emphasizing that the deduced programming rules are context dependent. These factors may complicate engineering the biosynthesis of a desired "unnatural product" but may also open additional avenues to create biosynthetic novelty based on fungal nonreduced polyketides.
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