{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:03:40Z","timestamp":1790701420731,"version":"4.1.0"},"reference-count":80,"publisher":"National Academy of Sciences","issue":"40","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["RM1GM145426"],"award-info":[{"award-number":["RM1GM145426"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM128742"],"award-info":[{"award-number":["R35GM128742"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023581","name":"NSF | NSF Graduate Research Fellowship Program","doi-asserted-by":"publisher","award":["AWD13127-2236414"],"award-info":[{"award-number":["AWD13127-2236414"]}],"id":[{"id":"10.13039\/100023581","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>\n                    Elucidating the biological origins and biosynthetic pathways of marine natural products remains a major challenge, particularly for compounds derived from microbial consortia. Here, we identify the marine cyanobacterial genus\n                    <jats:italic toggle=\"yes\">Dapis<\/jats:italic>\n                    as the source of the potent anticancer natural product dolastatin 15 using genome-resolved metagenomics. Reconstruction of two complete and two near-complete genomes provides genome-resolved characterization of the genus\n                    <jats:italic toggle=\"yes\">Dapis<\/jats:italic>\n                    , revealing extensive biosynthetic potential. Genome mining identified the dolastatin 15 biosynthetic gene cluster. Subsequent analyses reconstructed its pathway and uncovered a noncanonical five-domain nonribosomal peptide synthetase module containing an embedded 2-keto acid\u2013activating domain, revealing an unexpected architectural solution for incorporating 2-keto acid-derived hydroxy acid building blocks. Comparative and evolutionary analyses support a model in which this architecture may have arisen through recruitment of keto acid-activating domains and reduction of canonical adenylation domain features. We further biochemically and structurally characterize an\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    -methyltransferase that catalyzes formation of the characteristic methoxy pyrrolinone moiety, thereby validating a key terminal tailoring step in the proposed biosynthetic pathway. Together, these findings define the biosynthetic logic of dolastatin 15 and expand understanding of substrate activation and assembly-line diversification in nonribosomal peptide biosynthesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2615454123","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:18:26Z","timestamp":1790698706000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Biosynthetic origin of anticancer dolastatin 15 reveals a noncanonical NRPS architecture enabling 2-keto acid activation"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6803-044X","authenticated-orcid":false,"given":"Manyun","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery, and Development, University of Florida","place":["Gainesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hx57361","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biology, Princeton University","place":["Princeton"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8724-5627","authenticated-orcid":false,"given":"Hsin-Ying","family":"Tsai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery, and Development, University of Florida","place":["Gainesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1027-4649","authenticated-orcid":false,"given":"Cheng-Yu","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, University of Florida","place":["Gainesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1238-9415","authenticated-orcid":false,"given":"Jeremiah D.","family":"Batucan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery, and Development, University of Florida","place":["Gainesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5319-9834","authenticated-orcid":false,"given":"Campbell W.","family":"Eckhardt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery, and Development, University of Florida","place":["Gainesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam H. 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