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Malleicyprols were identified as important bacterial virulence factors, yet the biosynthetic origin of their cyclopropanol warhead has remained enigmatic. By a combination of mutational analysis and metabolomics we found that sulfonium acids, dimethylsulfoniumpropionate (DMSP) and gonyol, known as osmolytes and as crucial components in the global organosulfur cycle, are key intermediates en route to the cyclopropanol unit. Functional genetics and in\u2005vitro analyses uncover a specialized pathway to DMSP involving a rare prokaryotic SET\u2010domain methyltransferase for a cryptic methylation, and show that DMSP is loaded onto the NRPS\u2010PKS hybrid assembly line by an adenylation domain dedicated to zwitterionic starter units. Then, the megasynthase transforms DMSP into gonyol, as demonstrated by heterologous pathway reconstitution in <jats:italic>E. coli<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/anie.202003958","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T10:24:24Z","timestamp":1587464664000},"page":"13511-13515","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Sulfonium Acids Loaded onto an Unusual Thiotemplate Assembly Line Construct the Cyclopropanol Warhead of a <i>Burkholderia<\/i> Virulence Factor"],"prefix":"10.1002","volume":"59","author":[{"given":"Felix","family":"Trottmann","sequence":"first","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology (HKI)  Beutenbergstrasse 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keishi","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology (HKI)  Beutenbergstrasse 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7603-6232","authenticated-orcid":false,"given":"Jakob","family":"Franke","sequence":"additional","affiliation":[{"name":"Institute of Botany Leibniz University Hannover  30419 Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksa","family":"Stani\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Junior Research Group Biosynthetic Design of Natural Products Leibniz Institute for Natural Product Research and Infection Biology (HKI)  Beutenbergstrasse 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mie","family":"Ishida\u2010Ito","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology (HKI)  Beutenbergstrasse 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4919-2811","authenticated-orcid":false,"given":"Hajo","family":"Kries","sequence":"additional","affiliation":[{"name":"Junior Research Group Biosynthetic Design of Natural Products Leibniz Institute for Natural Product Research and Infection Biology (HKI)  Beutenbergstrasse 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Pohnert","sequence":"additional","affiliation":[{"name":"Institute for Inorganic and Analytical Chemistry Friedrich Schiller University Jena  07743 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0367-337X","authenticated-orcid":false,"given":"Christian","family":"Hertweck","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology (HKI)  Beutenbergstrasse 11a 07745 Jena Germany"},{"name":"Natural Product Chemistry Faculty of Biological Sciences Friedrich Schiller University Jena  07743 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,29]]},"reference":[{"key":"e_1_2_2_1_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2007.00949.x"},{"key":"e_1_2_2_2_1","first-page":"499","volume":"9","author":"Gilad J.","year":"2007","journal-title":"Isr. 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