ArticleNature2014
Structural rearrangements of a polyketide synthase module during its catalytic cycle.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed, 196 citations in OpenAlex.
- Condensation-independent intramodular translocation mechanism of the trans-AT polyketide synthase assembly line.Nature chemical biology · 2026Article
- Characterization of the ketoreductase domain of pikromycin module 2.Chemical science · 2026Article
- Gene conversion-associated successive engineering of modular polyketide synthases.Communications chemistry · 2025Article
- Visualizing acyl carrier protein interactions within a crosslinked type I polyketide synthase.Nature communications · 2025Article
- Mixing and Matching of Hybrid Megasynthases is a Hub for the Evolution of Metabolic Diversity in Cyanobacteria.Angewandte Chemie (International ed. in English) · 2025Article
- Structural basis for intermodular communication in assembly-line polyketide biosynthesis.Nature chemical biology · 2025Article
- Synthetic Biology in Natural Product Biosynthesis.Chemical reviews · 2025Review
- Directed Evolution of a Macrolide-Sensing Transcription Factor Biosensor for the Detection of Macrolactone Aglycones via "Effector Walking" and Efflux Pump Deletion.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
- Structure and Mechanisms of Assembly-Line Polyketide Synthases.Annual review of biochemistry · 2024Review
- Module-Based Polyketide Synthase Engineering forACS synthetic biology · 2023Review
- Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products.Chembiochem : a European journal of chemical biology · 2023Review
- Structure of a modular polyketide synthase reducing region.Structure (London, England : 1993) · 2023Article
- Enzymology of assembly line synthesis by modular polyketide synthases.Nature chemical biology · 2023Review
- C-N bond formation by a polyketide synthase.Nature communications · 2023Article
- Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition.Nature communications · 2023Article
- Marine Macrolides to Tackle Antimicrobial Resistance ofMarine drugs · 2022Review
- Priming enzymes from the pikromycin synthase reveal how assembly-line ketosynthases catalyze carbon-carbon chemistry.Structure (London, England : 1993) · 2022Article
- Solution structure of the type I polyketide synthase Pks13 from Mycobacterium tuberculosis.BMC biology · 2022Article
- Bifurcation drives the evolution of assembly-line biosynthesis.Nature communications · 2022Article
37 more citing papers are in PubMed but not listed here.
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11 authors at 1 institution in 1 country.
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Abstract
The polyketide synthase (PKS) mega-enzyme assembly line uses a modular architecture to synthesize diverse and bioactive natural products that often constitute the core structures or complete chemical entities for many clinically approved therapeutic agents. The architecture of a full-length PKS module from the pikromycin pathway of Streptomyces venezuelae creates a reaction chamber for the intramodule acyl carrier protein (ACP) domain that carries building blocks and intermediates between acyltransferase, ketosynthase and ketoreductase active sites (see accompanying paper). Here we determine electron cryo-microscopy structures of a full-length pikromycin PKS module in three key biochemical states of its catalytic cycle. Each biochemical state was confirmed by bottom-up liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry. The ACP domain is differentially and precisely positioned after polyketide chain substrate loading on the active site of the ketosynthase, after extension to the β-keto intermediate, and after β-hydroxy product generation. The structures reveal the ACP dynamics for sequential interactions with catalytic domains within the reaction chamber, and for transferring the elongated and processed polyketide substrate to the next module in the PKS pathway. During the enzymatic cycle the ketoreductase domain undergoes dramatic conformational rearrangements that enable optimal positioning for reductive processing of the ACP-bound polyketide chain elongation intermediate. These findings have crucial implications for the design of functional PKS modules, and for the engineering of pathways to generate pharmacologically relevant molecules.
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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.