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 α/β heterodimeric ketosynthase. Here, we present X-ray structures of all ternary complexes that constitute the minimal PKS system for anthraquinone biosynthesis in Photorhabdus 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.
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We acknowledge financial support from the Deutsche Forschungsgemeinschaft (DFG) SPP 1617 (H.B.B.) and SFB 1035 (V.R.I.K.) projects, as well as from the LOEWE program of the state of Hesse as part of the MegaSyn research cluster (H.B.B.). We thank the staff of beamline X06SA at the Paul Scherrer Institute (SLS, Villigen) for assistance during data collection, S. Fuchs for MALDI-MS analysis, and M. Karas for MALDI-MS access. The Swedish National Infrastructure for Computing (SNIC, 2019/2-3) provided computing time.
The authors declare no competing interests.
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Bräuer, A., Zhou, Q., Grammbitter, G.L.C. et al. Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis. Nat. Chem. 12, 755–763 (2020). https://doi.org/10.1038/s41557-020-0491-7
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