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Here, we elucidate the early stage biosynthetic pathway of the cytidyl\u2013cyclitol natural product K-563 and its derivatives. The cyclitol component is generated by the myo-inositol-1-phosphate synthase (MIPS) family enzyme KesM and is subsequently coupled to the cytidine moiety by KesL using cytidine 5\u2032-triphosphate (CTP), followed by further modifications catalyzed by the phosphatase KesI and the unique dehydrogenase complex KesJ\/KesK. The X-ray crystal structure and mutagenesis analyses reveal that KesL adopts the canonical fold of S-adenosyl-l-methionine (SAM) synthetases, which catalyze the adenosylation of l-methionine with adenosine 5\u2032-triphosphate (ATP) in primary metabolism, while the KesL active site is extensively remodeled to accept the cyclitol phosphate with CTP as an atypical substrate pair, thereby generating the cytidyl\u2013cyclitol core structure. This work not only expands the chemical logic of nucleoside biosynthesis but also demonstrates how the SAM synthetase-like protein scaffold is repurposed to catalyze an unusual nucleoside transfer reaction for specialized secondary metabolite assembly.<\/jats:p>","DOI":"10.1021\/jacs.6c11487","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:38:48Z","timestamp":1787359128000},"page":"37144-37153","source":"Crossref","is-referenced-by-count":0,"title":["A Repurposed\n                    <i>S<\/i>\n                    -Adenosyl-\n                    <scp>l<\/scp>\n                    -Methionine Synthetase\nMediates Cytidyl\u2013Cyclitol\nNatural Product Assembly"],"prefix":"10.1021","volume":"148","author":[{"given":"Zhongtian","family":"Yu","sequence":"first","affiliation":[{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-0033"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-0033"]},{"name":"Shenyang Pharmaceutical University , , 103 Wenhua Road , Shenhe, ,","place":["Shenyang, China, 110016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4071-3326","authenticated-orcid":true,"given":"Richiro","family":"Ushimaru","sequence":"additional","affiliation":[{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-0033"]},{"name":"Kyushu University , , 744 Motooka , Nishi-ku, ,","place":["Fukuoka, Japan, 819-0395"]},{"name":"FOREST, Japan Science and Technology Agency , ,","place":["Saitama, Japan, 332-0012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Shigemi","sequence":"additional","affiliation":[{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-0033"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2754-5858","authenticated-orcid":true,"given":"Takahiro","family":"Mori","sequence":"additional","affiliation":[{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-0033"]},{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-8657"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2575-3175","authenticated-orcid":true,"given":"Takayoshi","family":"Awakawa","sequence":"additional","affiliation":[{"name":"Riken, Center for Sustainable Resource Sciences , ,","place":["Saitama, Japan, 351-0198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6227-4627","authenticated-orcid":true,"given":"Koh","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-0033"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3640-888X","authenticated-orcid":true,"given":"Ikuro","family":"Abe","sequence":"additional","affiliation":[{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-0033"]},{"name":"The University of Tokyo , , ,","place":["Tokyo, Japan, 113-8657"]},{"name":"University of Toyama , , ,","place":["Toyama, Japan, 930-0194"]},{"name":"National Sun Yat-sen University , , ,","place":["Kaohsiung, Taiwan, 80424"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2026090312072618900_cit1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.imlet.2018.11.006","article-title":"Extracellular nucleotides and nucleosides\nas signalling molecules","volume":"205","author":"Giuliani","year":"2019","journal-title":"Immunol. 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