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While bacteria predominantly produce polyketides via modular type I polyketide synthases (PKSs), eukaryotic modular PKSs remain largely unexplored. Here, we report the functional characterization of a fungal modular PKS system from\n                    <jats:italic>Lasiodiplodia theobromae<\/jats:italic>\n                    through heterologous expression in\n                    <jats:italic>Aspergillus oryzae<\/jats:italic>\n                    , leading to the production of the antimalarial macrolide strasseriolide C (\n                    <jats:bold>1<\/jats:bold>\n                    ). Intriguingly, biosynthesis of\n                    <jats:bold>1<\/jats:bold>\n                    involves\n                    <jats:italic>C<\/jats:italic>\n                    \u2010methylation of the starter malonyl unit despite the absence of a methyltransferase domain in the loading module. Furthermore, module 2 of the PKS system contains an unusual arrangement of four consecutive acyl carrier protein (ACP) domains. Although the catalytic basis of this methylation remains unresolved, our isotope\u2010labeling experiments, mutational analyses, and in vitro biochemical assays support a model in which the malonyl unit loaded onto the module 2 ACPs is transferred to the loading ACP, where starter\u2010unit methylation is proposed to occur prior to chain initiation. Our study reveals unexpected biosynthetic logic and establishes a foundation for mechanistic studies and engineering of eukaryotic modular PKSs.\n                  <\/jats:p>","DOI":"10.1002\/anie.7344670","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:00:35Z","timestamp":1790820035000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of a Fungal Modular Polyketide Synthase System Reveals an Unusual Strategy for Polyketide Chain Initiation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-501X","authenticated-orcid":false,"given":"Qiaolin","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Chemistry City University of Hong Kong  Kowloon Hong Kong SAR 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