ArticleProceedings of the National Academy of Sciences of the United States of America2013
Rational reprogramming of fungal polyketide first-ring cyclization.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Black yeasts are efficient heterologous hosts for the production of a wide range of fungal polyketides.Nature chemical biology · 2026Article
- Resorcylic Acid Lactones and Isocoumarin Derivatives from the Marine-Associated Polar FungusMarine drugs · 2026Article
- 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
- Engineered and total biosynthesis of fungal specialized metabolites.Nature reviews. Chemistry · 2024Review
- Cloning and Functional Characterization of the Polyketide Synthases Based on Genome Mining ofFrontiers in microbiology · 2022Article
- Biosynthesis of 6-Hydroxymellein Requires a Collaborating Polyketide Synthase-like Enzyme.Angewandte Chemie (International ed. in English) · 2021Article
- 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
- Stereochemical determination of four 10-membered ring resorcylic acid lactones from the desert plant endophytic fungus Chaetosphaeronema hispidulum.The Journal of antibiotics · 2020Article
- Rhinoclactones A-E, Resorcylic Acid Analogs from Desert Plant Endophytic FungusMolecules (Basel, Switzerland) · 2019Article
- Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds.Journal of the American Chemical Society · 2019Article
- Modified substrate specificity of a methyltransferase domain by protein insertion into an adenylation domain of the bassianolide synthetase.Journal of biological engineering · 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
- Diversifying of Chemical Structure of NativeFrontiers in microbiology · 2018Review
- Antifungal and Cytotoxic β-Resorcylic Acid Lactones from a Paecilomyces Species.Journal of natural products · 2017Article
- Polyketide mimetics yield structural and mechanistic insights into product template domain function in nonreducing polyketide synthases.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Collaborative Biosynthesis of Maleimide- and Succinimide-Containing Natural Products by Fungal Polyketide Megasynthases.Journal of the American Chemical Society · 2017Article
- Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases.Fungal genetics and biology : FG & B · 2016Review
- Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase.Journal of the American Chemical Society · 2016Article
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12 authors.
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Abstract
Resorcylic acid lactones and dihydroxyphenylacetic acid lactones represent important pharmacophores with heat shock response and immune system modulatory activities. The biosynthesis of these fungal polyketides involves a pair of collaborating iterative polyketide synthases (iPKSs): a highly reducing iPKS with product that is further elaborated by a nonreducing iPKS (nrPKS) to yield a 1,3-benzenediol moiety bridged by a macrolactone. Biosynthesis of unreduced polyketides requires the sequestration and programmed cyclization of highly reactive poly-β-ketoacyl intermediates to channel these uncommitted, pluripotent substrates to defined subsets of the polyketide structural space. Catalyzed by product template (PT) domains of the fungal nrPKSs and discrete aromatase/cyclase enzymes in bacteria, regiospecific first-ring aldol cyclizations result in characteristically different polyketide folding modes. However, a few fungal polyketides, including the dihydroxyphenylacetic acid lactone dehydrocurvularin, derive from a folding event that is analogous to the bacterial folding mode. The structural basis of such a drastic difference in the way a PT domain acts has not been investigated until now. We report here that the fungal vs. bacterial folding mode difference is portable on creating hybrid enzymes, and we structurally characterize the resulting unnatural products. Using structure-guided active site engineering, we unravel structural contributions to regiospecific aldol condensations and show that reshaping the cyclization chamber of a PT domain by only three selected point mutations is sufficient to reprogram the dehydrocurvularin nrPKS to produce polyketides with a fungal fold. Such rational control of first-ring cyclizations will facilitate efforts to the engineered biosynthesis of novel chemical diversity from natural unreduced polyketides.
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