ArticleACS chemical biology2017
Inversion of Extender Unit Selectivity in the Erythromycin Polyketide Synthase by Acyltransferase Domain Engineering.
Article in ACS chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 68 citations in OpenAlex.
- Dissection and Engineering of Modular Polyketide Synthase Extender Unit Specificity Motifs.Chembiochem : a European journal of chemical biology · 2026Article
- Synthetic Biology in Natural Product Biosynthesis.Chemical reviews · 2025Review
- Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products.Chembiochem : a European journal of chemical biology · 2023Review
- Expanding Extender Substrate Selection for Unnatural Polyketide Biosynthesis by Acyltransferase Domain Exchange within a Modular Polyketide Synthase.Journal of the American Chemical Society · 2023Article
- Marine Macrolides to Tackle Antimicrobial Resistance ofMarine drugs · 2022Review
- Data Science-Driven Analysis of Substrate-Permissive Diketopiperazine Reverse Prenyltransferase NotF: Applications in Protein Engineering and Cascade Biocatalytic Synthesis of (-)-Eurotiumin A.Journal of the American Chemical Society · 2022Article
- Engineered biosynthesis of alkyne-tagged polyketides.Methods in enzymology · 2022Article
- Engineering the acyltransferase domain of epothilone polyketide synthase to alter the substrate specificity.Microbial cell factories · 2021Article
- Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase.Nature communications · 2021Article
- Bioengineering of Anti-Inflammatory Natural Products.ChemMedChem · 2021Review
- Biosynthesis of alkyne-containing natural products.RSC chemical biology · 2021Review
- Site directed mutagenesis as a precision tool to enable synthetic biology with engineered modular polyketide synthases.Synthetic and systems biotechnology · 2020Review
- Article
- Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis.Frontiers in molecular biosciences · 2020Review
- Engineering actinomycetes for biosynthesis of macrolactone polyketides.Microbial cell factories · 2019Review
- Diversification of polyketide structuresMedChemComm · 2019Review
- Recent advances in the discovery and combinatorial biosynthesis of microbial 14-membered macrolides and macrolactones.Journal of industrial microbiology & biotechnology · 2019Review
- Engineering the Substrate Specificity of a Modular Polyketide Synthase for Installation of Consecutive Non-Natural Extender Units.Journal of the American Chemical Society · 2019Article
- Extender Unit Promiscuity and Orthogonal Protein Interactions of an Aminomalonyl-ACP Utilizing Trans-Acyltransferase from Zwittermicin Biosynthesis.ACS chemical biology · 2018Article
- Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution.Nature communications · 2018Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Acyltransferase (AT) domains of polyketide synthases (PKSs) select extender units for incorporation into polyketides and dictate large portions of the structures of clinically relevant natural products. Accordingly, there is significant interest in engineering the substrate specificity of PKS ATs in order to site-selectively manipulate polyketide structure. However, previous attempts to engineer ATs have yielded mutant PKSs with relaxed extender unit specificity, rather than an inversion of selectivity from one substrate to another. Here, by directly screening the extender unit selectivity of mutants from active site saturation libraries of an AT from the prototypical PKS, 6-deoxyerythronolide B synthase, a set of single amino acid substitutions was discovered that dramatically impact the selectivity of the PKS with only modest reductions of product yields. One particular substitution (Tyr189Arg) inverted the selectivity of the wild-type PKS from its natural substrate toward a non-natural alkynyl-modified extender unit while maintaining more than twice the activity of the wild-type PKS with its natural substrate. The strategy and mutations described herein form a platform for combinatorial biosynthesis of site-selectively modified polyketide analogues that are modified with non-natural and non-native chemical functionality.
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