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All leinamycin family members bear a sulfur\u2010containing moiety which is essential for the anticancer activity exhibited by leinamycin. The key building blocks required for the incorporation of these functionalities are introduced in the final module of the polyketide synthase (PKS), which elegantly combines \u03b2\u2010branching and thiocysteine incorporation to generate a diverse library of sulfur\u2010based molecular scaffolds. Two acyl carrier proteins (ACPs) form a key didomain component of this module, but their amino acid sequence divergence has brought into question the common notion of functional equivalence. Here, we provide unprecedented functional evidence that these tandem ACPs play distinct roles in the final module of polyketide assembly. Using the weishanmycin biosynthetic pathway as a template, the in vitro reconstitution of key polyketide chain extension and \u03b2\u2010branching steps in this module has revealed strict functional selectivity for a single ACP. Furthermore, we propose a cryptic transacylation step must occur prior to polyketide off\u2010loading and cyclization. Altogether, these mechanistic investigations suggest that an atypical in\u2010series mechanism underpins sulfur incorporation in the leinamycin family, and provides significant progress towards delineating their late\u2010stage assembly.<\/jats:p>","DOI":"10.1002\/anie.202414165","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T05:56:26Z","timestamp":1727330186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Divergent Tandem Acyl Carrier Proteins Necessitate In\u2010Series Polyketide Processing in the Leinamycin Family"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6290-3809","authenticated-orcid":false,"given":"Annabel P.","family":"Phillips","sequence":"first","affiliation":[{"name":"School of Chemistry University of Bristol  Bristol BS8 1TS 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