Article abstract
Nature Biotechnology 26, 225 - 233 (2008)
Published online: 27 January 2008 | doi:10.1038/nbt1379
Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection
TuAnh Nguyen1,5, Keishi Ishida2,5, Holger Jenke-Kodama3, Elke Dittmann3, Cristian Gurgui1, Thomas Hochmuth1, Stefan Taudien4, Matthias Platzer4, Christian Hertweck2 & Jörn Piel1
Abstract
Modular polyketide synthases (PKSs) are giant bacterial enzymes that synthesize many polyketides of therapeutic value. In contrast to PKSs that provide acyltransferase (AT) activities in cis, trans-AT PKSs lack integrated AT domains and exhibit unusual enzymatic features with poorly understood functions in polyketide assembly. This has retarded insight into the assembly of products such as mupirocin, leinamycin and bryostatin 1. We show that trans-AT PKSs evolved in a fundamentally different fashion from cis-AT systems, through horizontal recruitment and assembly of substrate-specific ketosynthase (KS) domains. The insights obtained from analysis of these KS mosaics will facilitate both the discovery of novel polyketides by genome mining, as we demonstrate for the thailandamides of Burkholderia thailandensis, and the extraction of chemical information from short trans-AT PCR products, as we show using metagenomic DNA of marine sponges. Our data also suggest new strategies for dissecting polyketide biosynthetic pathways and engineering polyketide assembly.
- Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany.
- Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, D-07745 Jena, Germany.
- Department of Molecular Ecology, Institute of Biology, Humboldt University, Chausseestr. 117, D-10115 Berlin, Germany.
- Genome Analysis, Leibniz-Institute for Age Research–Fritz Lipmann Institute, Beutenbergstr. 11, Beutenberg Campus, D-07745 Jena, Germany.
- These authors contributed equally to this work.
Correspondence to: Jörn Piel1 e-mail: joern.piel@uni-bonn.de
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