ArticleJournal of the American Chemical Society2015
Functional Characterization of a Dehydratase Domain from the Pikromycin Polyketide Synthase.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Condensation-independent intramodular translocation mechanism of the trans-AT polyketide synthase assembly line.Nature chemical biology · 2026Article
- Molecular basis for depsipeptide HDAC inhibitor combinatorial biosynthesis.Nature communications · 2026Article
- Characterization of the ketoreductase domain of pikromycin module 2.Chemical science · 2026Article
- BGC-MAC and BGC-MAP: Attention-Based Models for Biosynthetic Gene Cluster Classification and Product Matching.Journal of chemical information and modeling · 2026Article
- Coenzyme A Tethering Mediates Dehydratase Substrate Promiscuity and Reaction Specificity in Platensimycin, Platencin, and Platensilin Biosynthesis.Biochemistry · 2025Article
- Elucidation of interface interactions between a dehydratase domain and an acyl carrier protein in cremimycin polyketide synthase.FEBS letters · 2025Article
- Modular polyketide synthase ketosynthases collaborate with upstream dehydratases to install double bonds.Chemical communications (Cambridge, England) · 2024Article
- Domain Truncation in Hispidin Synthase Orthologs from Non-Bioluminescent Fungi Does Not Lead to Hispidin Biosynthesis.International journal of molecular sciences · 2023Article
- Diene incorporation by a dehydratase domain variant in modular polyketide synthases.Nature chemical biology · 2022Article
- Functional analysis of the dehydratase domains of the PUFA synthase from Emiliania huxleyi in Escherichia coli and Arabidopsis thaliana.Biotechnology for biofuels and bioproducts · 2022Article
- Efficient biosynthesis of nucleoside cytokinin angustmycin A containing an unusual sugar system.Nature communications · 2021Article
- Site directed mutagenesis as a precision tool to enable synthetic biology with engineered modular polyketide synthases.Synthetic and systems biotechnology · 2020Review
- Hybrid Polyketides from aMarine drugs · 2019Article
- Structural insights into dehydratase substrate selection for the borrelidin and fluvirucin polyketide synthases.Journal of industrial microbiology & biotechnology · 2019Article
- pH-Rate profiles establish that polyketide synthase dehydratase domains utilize a single-base mechanism.Organic & biomolecular chemistry · 2018Article
- Trapping interactions between catalytic domains and carrier proteins of modular biosynthetic enzymes with chemical probes.Natural product reports · 2018Review
- Molecular Basis for Olefin Rearrangement in the Gephyronic Acid Polyketide Synthase.ACS chemical biology · 2018Article
- Stereospecific Formation of Z-Trisubstituted Double Bonds by the Successive Action of Ketoreductase and Dehydratase Domains from trans-AT Polyketide Synthases.Biochemistry · 2018Article
- Identification of a Thioesterase Bottleneck in the Pikromycin Pathway through Full-Module Processing of Unnatural Pentaketides.Journal of the American Chemical Society · 2017Article
- Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase.ACS chemical biology · 2016Article
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6 authors.
Funding
Abstract
Metabolic engineering of polyketide synthase (PKS) pathways represents a promising approach to natural products discovery. The dehydratase (DH) domains of PKSs, which generate an α,β-unsaturated bond through a dehydration reaction, have been poorly studied compared with other domains, likely because of the simple nature of the chemical reaction they catalyze and the lack of a convenient assay to measure substrate turnover. Herein we report the first steady-state kinetic analysis of a PKS DH domain employing LC-MS/MS analysis for product quantitation. PikDH2 was selected as a model DH domain. Its substrate specificity and mechanism were interrogated with a systematic series of synthetic triketide substrates containing a nonhydrolyzable thioether linkage as well as by site-directed mutagenesis, evaluation of the pH dependence of the catalytic efficiency (V(max)/K(M)), and kinetic characterization of a mechanism-based inhibitor. These studies revealed that PikDH2 converts d-alcohol substrates to trans-olefin products. The reaction is reversible with equilibrium constants ranging from 1.2 to 2. Moreover, the enzyme activity is robust, and PikDH2 was used on a preparative scale for the chemoenzymatic synthesis of unsaturated triketide products. PikDH2 was shown to possess remarkably strict substrate specificity and is unable to turn over substrates that are epimeric at the β-, γ-, or δ-position. We also demonstrated that PikDH2 has a key ionizable group with a pK(a) of 7.0 and can be irreversibly inactivated through covalent modification by a mechanism-based inhibitor, which provides a foundation for future structural studies to elucidate substrate-protein interactions.
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