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In stark contrast, the KS of the rhizoxin PKS branching module mediates a Michael addition, which sets the basis for a pharmacophoric \u03b4\u2010lactone moiety. The precise role of the KS was evaluated by site\u2010directed mutagenesis, chemical probes, and biotransformations. Biochemical and kinetic analyses helped to dissect branching and lactonization reactions and unequivocally assign the entire sequence to the KS. Probing the range of accepted substrates with diverse synthetic surrogates in vitro, we found that the KS tolerates defined acyl chain lengths to produce five\u2010 to seven\u2010membered lactones. These results show that the KS is multifunctional, as it catalyzes \u03b2\u2010branching and lactonization. Information on the increased product portfolio of the unusual, TE\u2010independent on\u2010line cyclization is relevant for synthetic biology approaches.<\/jats:p>","DOI":"10.1002\/anie.201804991","type":"journal-article","created":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T14:26:57Z","timestamp":1528900017000},"page":"11223-11227","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["On\u2010Line Polyketide Cyclization into Diverse Medium\u2010Sized Lactones by a Specialized Ketosynthase Domain"],"prefix":"10.1002","volume":"57","author":[{"given":"Srividhya","family":"Sundaram","sequence":"first","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology\u2014 Hans Kn\u00f6ll Institute  Beutenbergstrasse 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hak 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