Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-selective incorporation of fluorine in complex molecules have improved in recent years, approaches for the biosynthetic incorporation of fluorine in natural compounds are still rare. Here, we report a strategy to introduce fluorine into complex polyketides during biosynthesis. We exchanged the native acyltransferase domain of a polyketide synthase, which acts as the gatekeeper for the selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase. The resulting polyketide-synthase/fatty-acid-synthase hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl units in polyketide scaffolds. We demonstrate the feasibility of our approach in the chemoenzymatic synthesis of fluorinated 12- and 14-membered macrolactones and fluorinated derivatives of the macrolide antibiotics YC-17 and methymycin.
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This work was supported by a Lichtenberg grant of the Volkswagen Foundation to M.G. (grant number 85701). Further support was received from the LOEWE programme (Landes-Offensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz) of the state of Hesse conducted within the framework of the MegaSyn Research Cluster to M.G. We thank K. V. Huu and K. Karimi for MS analysis of acyl carrier proteins and K. S. Paithankar for proofreading the manuscript. Further, we are grateful to the Bode group for the extensive support in HPLC-MS and HPLC-HRMS analysis and J. Wirmer-Bartoschek and G. Sentis for support in NMR analysis. D.H.S. is grateful to National Institutes of Health grant R35 GM118101 and the Hans W. Vahlteich Professorship for support.
A.R. declares a financial interest as a cofounder of kez.biosolutions GmbH (Potsdam, Germany). All other authors declare no competing interests.
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Rittner, A., Joppe, M., Schmidt, J.J. et al. Chemoenzymatic synthesis of fluorinated polyketides. Nat. Chem. 14, 1000–1006 (2022). https://doi.org/10.1038/s41557-022-00996-z
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