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Compared with plant acyltransferases (ATs), bacterial tailoring ATs remain poorly understood. AntB from the antimycin pathway was previously reported to possess acyl\u2010donor promiscuity toward limited acyl\u2010CoA thioesters, yet its acyl\u2010acceptor promiscuity, structural basis, and catalytic mechanism had not been elucidated. Here, we systematically characterize AntB and uncover its remarkable dual substrate promiscuity. The enzyme accepts eight structurally diverse natural product acceptors\u2014including terpenoids, alkaloids, polyketides, and aromatics\u2014and supports iterative acylation, while also processing 43 chemically distinct acyl donors, including 22 previously unreported. Structural analysis revealed the molecular basis of its dual substrate promiscuity and catalysis. Engineering afforded the S17A\/M265L variant with a 4.45\u2010fold increase in activity toward\n                    <jats:bold>SPN\u2010J<\/jats:bold>\n                    acylation. To harness this catalytic flexibility, we developed a one\u2010pot biocatalytic platform by combining AntB with engineered acyl\u2010CoA synthetases UkaQ\n                    <jats:sup>FAV<\/jats:sup>\n                    and AliA\n                    <jats:sub>100<\/jats:sub>\n                    for in situ acyl\u2010CoA regeneration. Application of this system to the late\u2010stage modification of the agrochemical precursor deacyl\u2010\n                    <jats:bold>UK\u20102A<\/jats:bold>\n                    generated a panel of acylated analogues, including three novel derivatives with enhanced antifungal activity. This study advances understanding of bacterial tailoring ATs and establishes AntB as a versatile biocatalyst for late\u2010stage natural product diversification.\n                  <\/jats:p>","DOI":"10.1002\/anie.9826344","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:47:20Z","timestamp":1790826440000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural and Mechanistic Basis of Dual Substrate Promiscuity in the Acyltransferase AntB Enables Late\u2010Stage Diversification of Natural Products"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3614-0125","authenticated-orcid":false,"given":"Mengmeng","family":"Zheng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"},{"name":"Shanghai Key Laboratory of Bio\u2010Energy Crops Synthetic Biology Research Center School of Life Sciences Shanghai University  Shanghai China"},{"name":"Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5404-0694","authenticated-orcid":false,"given":"Yuhan","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"},{"name":"Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"},{"name":"Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong 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