ArticleJournal of the American Chemical Society2019
Engineering the Substrate Specificity of a Modular Polyketide Synthase for Installation of Consecutive Non-Natural Extender Units.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Dissection and Engineering of Modular Polyketide Synthase Extender Unit Specificity Motifs.Chembiochem : a European journal of chemical biology · 2026Article
- Graph neural networks can predict ketosynthase substrate specificity.Scientific reports · 2026Article
- Investigation of Domain-Domain Interaction between Acyl Carrier Protein and Thioesterase in Modular Polyketide Synthases.JACS Au · 2026Article
- Merging the computational design of chimeric type I polyketide synthases with enzymatic pathways for chemical biosynthesis.Nature communications · 2025Article
- Engineering of a Malonyl-CoA Ligase for Production of Fluorinated Polyketide Extender Units.Chembiochem : a European journal of chemical biology · 2024Article
- The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds.Communications chemistry · 2024Article
- Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products.Chembiochem : a European journal of chemical biology · 2023Review
- Biosynthesis-Guided Discovery and Engineering of α-Pyrone Natural Products from Type I Polyketide Synthases.ACS chemical biology · 2023Article
- Enzymology of assembly line synthesis by modular polyketide synthases.Nature chemical biology · 2023Review
- Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition.Nature communications · 2023Article
- Priming enzymes from the pikromycin synthase reveal how assembly-line ketosynthases catalyze carbon-carbon chemistry.Structure (London, England : 1993) · 2022Article
- Chemoenzymatic synthesis of fluorinated polyketides.Nature chemistry · 2022Article
- Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase.Nature communications · 2021Article
- Bioengineering of Anti-Inflammatory Natural Products.ChemMedChem · 2021Review
- Protein engineering for natural product biosynthesis and synthetic biology applications.Protein engineering, design & selection : PEDS · 2021Review
- Synthetic biology enabling access to designer polyketides.Current opinion in chemical biology · 2020Review
- Probing Selectivity and Creating Structural Diversity Through Hybrid Polyketide Synthases.Angewandte Chemie (International ed. in English) · 2020Article
- Understanding Substrate Selectivity of Phoslactomycin Polyketide Synthase by Using Reconstituted in Vitro Systems.Chembiochem : a European journal of chemical biology · 2020Article
- Article
- Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis.Frontiers in molecular biosciences · 2020Review
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5 authors.
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Abstract
There is significant interest in diversifying the structures of polyketides to create new analogues of these bioactive molecules. This has traditionally been done by focusing on engineering the acyltransferase (AT) domains of polyketide synthases (PKSs) responsible for the incorporation of malonyl-CoA extender units. Non-natural extender units have been utilized by engineered PKSs previously; however, most of the work to date has been accomplished with ATs that are either naturally promiscuous and/or located in terminal modules lacking downstream bottlenecks. These limitations have prevented the engineering of ATs with low native promiscuity and the study of any potential gatekeeping effects by domains downstream of an engineered AT. In an effort to address this gap in PKS engineering knowledge, the substrate preferences of the final two modules of the pikromycin PKS were compared for several non-natural extender units and through active site mutagenesis. This led to engineering of the methylmalonyl-CoA specificity of both modules and inversion of their selectivity to prefer consecutive non-natural derivatives. Analysis of the product distributions of these bimodular reactions revealed unexpected metabolites resulting from gatekeeping by the downstream ketoreductase and ketosynthase domains. Despite these new bottlenecks, AT engineering provided the first full-length polyketide products incorporating two non-natural extender units. Together, this combination of tandem AT engineering and the identification of previously poorly characterized bottlenecks provides a platform for future advancements in the field.
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