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Substantial efforts were made to improve the supply of this scarce substance through chemical synthesis and mariculture, however, sustainable production has yet to be achieved. Recent microbiome sequencing suggested that bacterial producers are responsible for all\n                    <jats:italic>M. hentscheli<\/jats:italic>\n                    bioactive compounds, but the identity of the peloruside producer remained unknown. Furthermore, a candidate peloruside polyketide synthase (PKS) was identified in silico, but its highly aberrant architecture prevented a confident biosynthetic prediction for the pharmacologically important exocyclic double bond. Here, we reveal an unusually complex modular PKS pathway comprising nonelongating ketosynthases (KSs), two internal thioesterases (TEs), and an acetyl coenzyme A ligase that orchestrate\n                    <jats:italic>O<\/jats:italic>\n                    \u2010acetylation\/elimination, acetyl\u2010CoA recycling, and configurational proof\u2010reading to facilitate selective\n                    <jats:italic>Z<\/jats:italic>\n                    \u2010double bond incorporation. The first internal TE falls into a previously characterized\n                    <jats:italic>O<\/jats:italic>\n                    \u2010acylating TE family but contains key amino acid substitutions that facilitate bifunctional acylation\/elimination activity. Furthermore, we identified the peloruside producer as \u2018\n                    <jats:italic>Candidatus<\/jats:italic>\n                    Pelorusia occulta\u2019, a member of the biochemically underexplored Lentisphaeria class within the phylum Verrucomicrobiota. This work provides the biochemical and microbiological foundation for heterologous peloruside production.\n                  <\/jats:p>","DOI":"10.1002\/anie.2011872","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:59:08Z","timestamp":1788440348000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Noncanonical Peloruside A Biosynthesis by an Uncultivated Verrucomicrobiota Symbiont"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-0538","authenticated-orcid":false,"given":"Amy E.","family":"Fraley","sequence":"first","affiliation":[{"name":"Department of Biology Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"},{"name":"Department of Chemistry and Applied Biosciences Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6648-2434","authenticated-orcid":false,"given":"Michael","family":"Rust","sequence":"additional","affiliation":[{"name":"Department of Biology Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"},{"name":"Syngenta Crop Protection AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Biology Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2331-2983","authenticated-orcid":false,"given":"Ida R.","family":"Hipfinger","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Applied Biosciences Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J. N.","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Department of Biology Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cora L.","family":"Dieterich","sequence":"additional","affiliation":[{"name":"Department of Biology Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"},{"name":"Blue Matter Consulting  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6434-3745","authenticated-orcid":false,"given":"Christopher M.","family":"Field","sequence":"additional","affiliation":[{"name":"Department of Biology Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Z\u00fcrich  Z\u00fcrich Switzerland"},{"name":"Universit\u00e4tsspital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Page","sequence":"additional","affiliation":[{"name":"Aquaculture Coasts and Oceans National Institute of Water and Atmospheric Research Ltd.  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