ArticleJournal of the American Chemical Society2017
Identification of a Thioesterase Bottleneck in the Pikromycin Pathway through Full-Module Processing of Unnatural Pentaketides.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Investigation of Domain-Domain Interaction between Acyl Carrier Protein and Thioesterase in Modular Polyketide Synthases.JACS Au · 2026Article
- Skeletal editing via multi-step engineering of a modular polyketide synthase.Nature communications · 2026Article
- Article
- Characterization of the ketoreductase domain of pikromycin module 2.Chemical science · 2026Article
- Establishing Selectivity Trends with Reactions of Thioesterases and Semi-Synthetic Polyketides.Journal of the American Chemical Society · 2025Article
- Plug-and-play engineering of modular polyketide synthases.Nature chemical biology · 2025Article
- Synthetic Biology in Natural Product Biosynthesis.Chemical reviews · 2025Review
- Directed Evolution of a Modular Polyketide Synthase Thioesterase for Generation of a Hybrid Macrocyclic Ring System.ACS catalysis · 2025Article
- Refactoring the pikromycin synthase for the modular biosynthesis of macrolide antibiotics in E. coli.Research square · 2025Article
- Substrate Trapping in Polyketide Synthase Thioesterase Domains: Structural Basis for Macrolactone Formation.ACS catalysis · 2024Article
- Article
- Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products.Chembiochem : a European journal of chemical biology · 2023Review
- Chemoenzymatic synthesis of fluorinated polyketides.Nature chemistry · 2022Article
- Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead.Nature chemical biology · 2022Article
- Biosynthetic Cyclization Catalysts for the Assembly of Peptide and Polyketide Natural Products.ChemCatChem · 2021Article
- Probing Selectivity and Creating Structural Diversity Through Hybrid Polyketide Synthases.Angewandte Chemie (International ed. in English) · 2020Article
- Site directed mutagenesis as a precision tool to enable synthetic biology with engineered modular polyketide synthases.Synthetic and systems biotechnology · 2020Review
- A Versatile Chemoenzymatic Synthesis for the Discovery of Potent Cryptophycin Analogs.ACS chemical biology · 2020Article
- Local Adaptation of Bacterial Symbionts within a Geographic Mosaic of Antibiotic Coevolution.Applied and environmental microbiology · 2019Article
- Engineering enzymatic assembly lines to produce new antibiotics.Current opinion in microbiology · 2019Review
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3 authors.
Funding
Abstract
Polyketide biosynthetic pathways have been engineered to generate natural product analogs for over two decades. However, manipulation of modular type I polyketide synthases (PKSs) to make unnatural metabolites commonly results in attenuated yields or entirely inactive pathways, and the mechanistic basis for compromised production is rarely elucidated since rate-limiting or inactive domain(s) remain unidentified. Accordingly, we synthesized and assayed a series of modified pikromycin (Pik) pentaketides that mimic early pathway engineering to probe the substrate tolerance of the PikAIII-TE module in vitro. Truncated pentaketides were processed with varying efficiencies to corresponding macrolactones, while pentaketides with epimerized chiral centers were poorly processed by PikAIII-TE and failed to generate 12-membered ring products. Isolation and identification of extended but prematurely offloaded shunt products suggested that the Pik thioesterase (TE) domain has limited substrate flexibility and functions as a gatekeeper in the processing of unnatural substrates. Synthesis of an analogous hexaketide with an epimerized nucleophilic hydroxyl group allowed for direct evaluation of the substrate stereoselectivity of the excised TE domain. The epimerized hexaketide failed to undergo cyclization and was exclusively hydrolyzed, confirming the TE domain as a key catalytic bottleneck. In an accompanying paper , we engineer the standalone Pik thioesterase to yield a thioesterase (TE
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