ArticleACS chemical biology2013
Structural studies of an A2-type modular polyketide synthase ketoreductase reveal features controlling α-substituent stereochemistry.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- Engineering Polyketide Stereocenters with Ketoreductase Domain Exchanges.Journal of the American Chemical Society · 2025Article
- Distinct Acyl Carrier Protein Docking Sites Help Mediate the Opposite Stereoselectivities of A- and B-type Modular Polyketide Synthase Ketoreductases.Biochemistry · 2025Article
- Architecture of full-length type I modular polyketide synthases revealed by X-ray crystallography, cryo-electron microscopy, and AlphaFold2.Natural product reports · 2024Review
- Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain.Beilstein journal of organic chemistry · 2024Article
- Structure of a modular polyketide synthase reducing region.Structure (London, England : 1993) · 2023Article
- C-N bond formation by a polyketide synthase.Nature communications · 2023Article
- Article
- Modular polyketide synthase contains two reaction chambers that operate asynchronously.Science (New York, N.Y.) · 2021Article
- Site directed mutagenesis as a precision tool to enable synthetic biology with engineered modular polyketide synthases.Synthetic and systems biotechnology · 2020Review
- Structural basis of keto acid utilization in nonribosomal depsipeptide synthesis.Nature chemical biology · 2020Article
- Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis.Frontiers in molecular biosciences · 2020Review
- Engineering enzymatic assembly lines to produce new antibiotics.Current opinion in microbiology · 2019Review
- The architectures of iterative type I PKS and FAS.Natural product reports · 2018Review
- Substrate-bound structures of a ketoreductase from amphotericin modular polyketide synthase.Journal of structural biology · 2018Article
- Engineered polyketides: Synergy between protein and host level engineering.Synthetic and systems biotechnology · 2017Review
- Structural and Functional Trends in Dehydrating Bimodules from trans-Acyltransferase Polyketide Synthases.Structure (London, England : 1993) · 2017Article
- Elucidation of the Stereospecificity of C-Methyltransferases from trans-AT Polyketide Synthases.Journal of the American Chemical Society · 2017Article
- Mechanism and Stereochemistry of Polyketide Chain Elongation and Methyl Group Epimerization in Polyether Biosynthesis.Journal of the American Chemical Society · 2017Article
- Towards Precision Engineering of Canonical Polyketide Synthase Domains: Recent Advances and Future Prospects.Molecules (Basel, Switzerland) · 2017Review
- Polyketide stereocontrol: a study in chemical biology.Beilstein journal of organic chemistry · 2017Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Modular polyketide synthase ketoreductases often set two stereocenters when reducing intermediates in the biosynthesis of a complex polyketide. Here we report the 2.55-Å resolution structure of an A2-type ketoreductase from the 11th module of the amphotericin polyketide synthase that sets a combination of l-α-methyl and l-β-hydroxyl stereochemistries and represents the final catalytically competent ketoreductase type to be structurally elucidated. Through structure-guided mutagenesis a double mutant of an A1-type ketoreductase was generated that functions as an A2-type ketoreductase on a diketide substrate analogue, setting an α-alkyl substituent in an l-orientation rather than in the d-orientation set by the unmutated ketoreductase. When the activity of the double mutant was examined in the context of an engineered triketide lactone synthase, the anticipated triketide lactone was not produced even though the ketoreductase-containing module still reduced the diketide substrate analogue as expected. These findings suggest that re-engineered ketoreductases may be catalytically outcompeted within engineered polyketide synthase assembly lines.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.