{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:06:00Z","timestamp":1790820360991,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82304326"],"award-info":[{"award-number":["82304326"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273806"],"award-info":[{"award-number":["82273806"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82622116"],"award-info":[{"award-number":["82622116"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81921001"],"award-info":[{"award-number":["81921001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFA0914100"],"award-info":[{"award-number":["2023YFA0914100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Flavonoid 6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosides from\n                    <jats:italic>Carthamus tinctorius<\/jats:italic>\n                    (safflower) represent a unique class of potential antithrombotic agents. However, their pharmaceutical development has been hindered by limited natural resources. In this study, we characterized four key biosynthetic enzymes from\n                    <jats:italic>C. tinctorius<\/jats:italic>\n                    : Ct6OGT (6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosyltransferase), Ct7OGT (7\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosyltransferase), Ct3OGT (3\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosyltransferase), and CtFLS (flavonol synthase). Among them, Ct6OGT is the first identified high\u2010regioselectivity flavonoid 6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosyltransferase. By combining these enzymes with upstream genes identified from safflower, we established an in vitro enzymatic approach for the synthesis of 6\u2010hydroxykaempferol 3,6,7\u2010tri\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosides. Notably, enzymatic assays demonstrated that the 3,6,7\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010triglycosides were synthesized via a sequential linear glycosylation pathway, in the order of 6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010, 7\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010, and finally 3\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosylation. Through combinatorial biosynthesis, we further produced 26 flavonoid 6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosides, including naturally occurring compounds from\n                    <jats:italic>C. tinctorius<\/jats:italic>\n                    and novel analogs. Subsequent evaluation in a zebrafish model revealed these flavonoid 6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosides exhibited antithrombotic activities, with 6\u2010hydroxylation and 6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosylation remarkably enhancing the potency. This work represents the first report of an enzymatic synthetic method for flavonoid 6\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010glycosides, and provides a valuable foundation for their future drug development.\n                  <\/jats:p>","DOI":"10.1002\/anie.8881851","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:53:21Z","timestamp":1790819601000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combinatorial Biosynthesis of Antithrombotic Flavonoid 6\u2010\n                    <i>O<\/i>\n                    \u2010Glycosides From\n                    <i>Carthamus tinctorius<\/i>"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7875-0704","authenticated-orcid":false,"given":"Zi\u2010Long","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"},{"name":"Peking University\u2010Yunnan Baiyao International Medical Research Center Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Ye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Gang","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5684-8655","authenticated-orcid":false,"given":"Hao\u2010Tian","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4777-4261","authenticated-orcid":false,"given":"Xiao\u2010Dong","family":"Luo","sequence":"additional","affiliation":[{"name":"Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry For Natural Resource, Ministry of Education and Yunnan Province School of Chemical Science and Technology Yunnan University  Kunming China"},{"name":"Southwest United Graduate School  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-2380","authenticated-orcid":false,"given":"Min","family":"Ye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"},{"name":"Peking University\u2010Yunnan Baiyao International Medical Research Center Peking University  Beijing China"},{"name":"Southwest United Graduate School  Kunming China"},{"name":"Institute For Safflower Industry Research of Shihezi University \/ Pharmacy School of Shihezi University \/ Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education Shihezi University  Shihezi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.122.035498"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001145"},{"key":"e_1_2_8_4_1","first-page":"e41","article-title":"2025 Heart Disease and Stroke Statistics: A Report of us and Global Data From the american heart association","volume":"151","author":"C. Amer Heart Assoc, C. Prevention Stat and C. Stroke Stat","year":"2025","journal-title":"Circulation"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2021.12.017"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05165-3"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105737"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.19524"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113462"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2013.10.050"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2017.11.069"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2018.11.006"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9FO00896A"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2024.140218"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2016.01.023"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2016.12.027"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2008.03.046"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201002883\u2010z"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11434\u2010016\u20101136\u20105"},{"key":"e_1_2_8_20_1","article-title":"Current Advances of Carthamus tinctorius L.: A Review of Its Application and Molecular Regulation of Flavonoid Biosynthesis","volume":"3","author":"Wu Z. H.","year":"2024","journal-title":"Medicine Plant Biology"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molp.2017.08.009"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201059774\u20103"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biotechadv.2020.107550"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.04.001"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2SC06504E"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/tpj.70213"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25105546"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202402546"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/1755\u20105922.12233"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102014\u201005\u2010378638"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2011.04520.x"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.248542"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2014.09.003"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12140"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.8881851","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.8881851","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.8881851","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:53:22Z","timestamp":1790819602000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.8881851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":33,"alternative-id":["10.1002\/anie.8881851"],"URL":"https:\/\/doi.org\/10.1002\/anie.8881851","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"assertion":[{"value":"2025-12-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e8881851"}}