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Journal Article

Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis


Bode,  Helge B.
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;
Goethe-Universität Frankfurt am Main, External Organizations;

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Braeuer, A., Zhou, Q., Grammbitter, G. L. C., Schmalhofer, M., Ruehl, M., Kaila I, V. R., et al. (2020). Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis. NATURE CHEMISTRY, 12(8). doi:10.1038/s41557-020-0491-7.

Cite as: https://hdl.handle.net/21.11116/0000-000A-0504-C
The invariable core of a type II polyketide synthase has been characterized using X-ray crystallography, simulations, mutagenesis experiments and functional assays. The characterization of the ternary acyl carrier protein complexes provides a mechanistic understanding of the reactivity and could inform future engineering of this complex biosynthetic machinery.
Type II polyketide synthases (PKSs) are multi-enzyme complexes that produce secondary metabolites of medical relevance. Chemical backbones of such polyketides are produced by minimal PKS systems that consist of a malonyl transacylase, an acyl carrier protein and an alpha/beta heterodimeric ketosynthase. Here, we present X-ray structures of all ternary complexes that constitute the minimal PKS system for anthraquinone biosynthesis inPhotorhabdus luminescens. In addition, we characterize this invariable core using molecular simulations, mutagenesis experiments and functional assays. We show that malonylation of the acyl carrier protein is accompanied by major structural rearrangements in the transacylase. Principles of an ongoing chain elongation are derived from the ternary complex with a hexaketide covalently linking the heterodimeric ketosynthase with the acyl carrier protein. Our results for the minimal PKS system provide mechanistic understanding of PKSs and a fundamental basis for engineering PKS pathways for future applications.