Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis

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. He...

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Bibliographic Details
Published in:	Nature chemistry 2020-08, Vol.12 (8), p.755-763
Main Authors:	Bräuer, Alois, Zhou, Qiuqin, Grammbitter, Gina L C, Schmalhofer, Maximilian, Rühl, Michael, Kaila, Ville R I, Bode, Helge B, Groll, Michael
Format:	Article
Language:	eng
Subjects:	Acyl carrier protein Acyl Carrier Protein - metabolism Anthraquinone Anthraquinones Anthraquinones - chemistry Anthraquinones - metabolism Binding Sites Biosynthesis Crystallography Crystallography, X-Ray Density Functional Theory Elongated structure Malonates - metabolism Metabolites Molecular Dynamics Simulation Multigene Family - genetics Mutagenesis Photorhabdus - enzymology Photorhabdus - metabolism Polyketide synthase Polyketide Synthases - chemistry Polyketide Synthases - genetics Polyketide Synthases - metabolism Polyketides Polyketides - chemistry Polyketides - metabolism Protein Structure, Quaternary Proteins Recombinant Proteins - biosynthesis Recombinant Proteins - chemistry Recombinant Proteins - isolation & purification Secondary metabolites X-ray crystallography
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Summary:	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.
ISSN:	1755-4330 1755-4349 1755-4349