{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:01:24Z","timestamp":1790604084260,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"40","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"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":["22522111 22361142832 22271212"],"award-info":[{"award-number":["22522111 22361142832 22271212"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Aromatic polyketides have gained significant attention as prominent plant\u2010derived polyphenol molecules in recent years owing to their multi\u2010faceted therapeutic potentials against a variety of diseases. However, the introduction of unique fluorine atoms into the core structure of aromatic polyketides has received limited exploration thus far. In this study, a series of new\u2010to\u2010nature fluorinated aromatic polyketides, including resveratrol, naringenin chalcone, bisnoyangonin, and benzalactone, were obtained from readily available fluoro\u2010tyrosines in\n                    <jats:italic>E. coli<\/jats:italic>\n                    via a multi\u2010enzyme cascade pathway. A series of combinational optimization strategies, including metabolic regulations, double protein fusion (4CL::III\u2010PKS and MatB::III\u2010PKS), and directed evolution of the rate\u2010limiting enzymes, were conducted to improve the production of fluoro\u2010aromatic polyketides, thus enhancing the titers to &gt;200\u00a0mg\/L from an initial \u223c10\u00a0mg\/L. When both sides of the phenolic hydroxyl group of 4\u2010coumaroyl\u2010CoA contain fluorine atoms, a novel catalytic pathway of STS and CHS in synthesizing methyl ketone structures is unlocked, namely the \u201c\n                    <jats:italic>proximal fluorine\u2010induced III\u2010PKS catalytic truncation<\/jats:italic>\n                    \u201d. Further post\u2010functionalizations by enzymatic glycosylation reaction and chemocatalytic Friedel\u2013Crafts\u2010type reaction provided the corresponding fluorinated derivatives of polyphenolic natural products (piceid and arahypin).\n                  <\/jats:p>","DOI":"10.1002\/anie.3691732","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:18:11Z","timestamp":1785428291000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biosynthesis of Fluorinated Aromatic Polyketides Through Directed Evolution of Fused Type III Polyketide Synthase"],"prefix":"10.1002","volume":"65","author":[{"given":"Ze\u2010Long","family":"Mei","sequence":"first","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Biology Frontiers Science Center For Synthetic Biology (Ministry of Education) Tianjin University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Xin","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Biology Frontiers Science Center For Synthetic Biology (Ministry of Education) Tianjin University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9923-0951","authenticated-orcid":false,"given":"Zhoutong","family":"Sun","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Industrial Biotechnology of Chinese Academy of Sciences National Technology Innovation Center of Synthetic Biology  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3902-6799","authenticated-orcid":false,"given":"Jun\u2010An","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Biology Frontiers Science Center For Synthetic Biology (Ministry of Education) Tianjin University  Tianjin P. R. China"},{"name":"School of Synthetic Biology and Biomanufacturing State Key Laboratory of Synthetic Biology Tianjin University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0251-0456","authenticated-orcid":false,"given":"Fa\u2010Guang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Biology Frontiers Science Center For Synthetic Biology (Ministry of Education) Tianjin University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2017.08.002"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2060"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.01.017"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2013.03.038"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0NP00030B"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jsfa.10152"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2009.09.005"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00253\u2010016\u20107723\u20101"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.833920"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1039\/B100917F"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201600522"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014\u20105793(72)80679\u20103"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00029856"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003\u20109861(75)90319\u20107"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432\u20101327.2001.02255.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02796\u201009"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2013.07.030"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.8b05014"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201000044"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr500689b"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1131943"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00258"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01788"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/416279a"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978\u20100\u201012\u2010394291\u20103.00003\u20104"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk8464"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44160\u2010024\u201000507\u20107"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44160\u2010024\u201000536\u20102"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.4c00945"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c03499"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202524744"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/np900719u"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2356"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0622094"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.12.029"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.synbio.2022.10.005"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf981024g"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27196474"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201100256"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.7b03440"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010022\u201000931\u20102"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CC08503C"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2011.02.002"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00425\u2010018\u20102965\u2010z"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1128\/aem.02186\u201010"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10295\u2010007\u20100229\u20101"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1105\/tpc.109.072652"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201021734\u2010y"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2015.03.018"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.procbio.2023.11.004"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1128\/genomeA.00221\u201017"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0101492"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/11553"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202212440"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2017.01.006"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/sb300037w"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200500767"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biortech.2023.129129"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2012.08.017"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV119.006129"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21060806"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.3691732","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.3691732","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.3691732","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:21:42Z","timestamp":1790601702000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.3691732"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":61,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2026,9,28]]}},"alternative-id":["10.1002\/anie.3691732"],"URL":"https:\/\/doi.org\/10.1002\/anie.3691732","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]},"assertion":[{"value":"2026-05-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e3691732"}}