ArticleJournal of the American Chemical Society2014
Modeling linear and cyclic PKS intermediates through atom replacement.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 30 citations in OpenAlex.
- Elucidating the Iterative Elongation Mechanism in a Type III Polyketide Synthase.Journal of the American Chemical Society · 2025Article
- Enzymology of standalone elongating ketosynthases.Chemical science · 2022Review
- Molecular Basis for Polyketide Ketoreductase-Substrate Interactions.International journal of molecular sciences · 2020Article
- A Light-Activated Acyl Carrier Protein "Trap" for Intermediate Capture in Type II Iterative Polyketide Biocatalysis.Chemistry (Weinheim an der Bergstrasse, Germany) · 2019Article
- Computational structural enzymology methodologies for the study and engineering of fatty acid synthases, polyketide synthases and nonribosomal peptide synthetases.Methods in enzymology · 2019Article
- Trapping interactions between catalytic domains and carrier proteins of modular biosynthetic enzymes with chemical probes.Natural product reports · 2018Review
- Type II fatty acid and polyketide synthases: deciphering protein-protein and protein-substrate interactions.Natural product reports · 2018Review
- An Oxetane-Based Polyketide Surrogate To Probe Substrate Binding in a Polyketide Synthase.Journal of the American Chemical Society · 2018Article
- 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
- An unusual intramolecularTetrahedron · 2016Article
- Recognition of extended linear and cyclised polyketide mimics by a type II acyl carrier protein.Chemical science · 2016Article
- Structure and Substrate Sequestration in the Pyoluteorin Type II Peptidyl Carrier Protein PltL.Journal of the American Chemical Society · 2015Article
- Probing the structure and function of acyl carrier proteins to unlock the strategic redesign of type II polyketide biosynthetic pathways.The Journal of biological chemistryReview
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
The mechanistic details of many polyketide synthases (PKSs) remain elusive due to the instability of transient intermediates that are not accessible via conventional methods. Here we report an atom replacement strategy that enables the rapid preparation of polyketone surrogates by selective atom replacement, thereby providing key substrate mimetics for detailed mechanistic evaluations. Polyketone mimetics are positioned on the actinorhodin acyl carrier protein (actACP) to probe the underpinnings of substrate association upon nascent chain elongation and processivity. Protein NMR is used to visualize substrate interaction with the actACP, where a tetraketide substrate is shown not to bind within the protein, while heptaketide and octaketide substrates show strong association between helix II and IV. To examine the later cyclization stages, we extended this strategy to prepare stabilized cyclic intermediates and evaluate their binding by the actACP. Elongated monocyclic mimics show much longer residence time within actACP than shortened analogs. Taken together, these observations suggest ACP-substrate association occurs both before and after ketoreductase action upon the fully elongated polyketone, indicating a key role played by the ACP within PKS timing and processivity. These atom replacement mimetics offer new tools to study protein and substrate interactions and are applicable to a wide variety of PKSs.
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