{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:16:13Z","timestamp":1788455773554,"version":"build-2803163510"},"reference-count":48,"publisher":"American Chemical Society (ACS)","issue":"34","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/na","name":"the Research Program of State Key Laboratory of Green Chemical Synthesis and Conversion","doi-asserted-by":"publisher","award":["SKLGSC-ZZ-202628"],"award-info":[{"award-number":["SKLGSC-ZZ-202628"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Organophosphorus compounds constitute an important class of functional molecules with broad relevance in synthesis, catalysis, and medicinal chemistry. Despite their importance, biocatalytic C\u2013P bond formation remains rare, with only a limited number of examples identified from natural product biosynthesis. Here we report a previously unexplored biocatalytic platform for C\u2013P bond construction through flavin-dependent enzyme-catalyzed intermolecular radical coupling involving phosphinoyl radical intermediates. The transformation is directly driven by ground-state FMNhq, and protein engineering enables stereodivergent control over the formal hydrophosphinylation of aryl-substituted alkenes, acrylate-derived electron-deficient alkenes, and representative unactivated alkenes. This work brings phosphinoyl radical chemistry into flavin-dependent radical biocatalysis and provides a new strategy for the asymmetric synthesis of organophosphorus compounds.<\/jats:p>","DOI":"10.1021\/jacs.6c08848","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T20:14:10Z","timestamp":1787343250000},"page":"36842-36853","source":"Crossref","is-referenced-by-count":0,"title":["Ground-State\nFlavin-Dependent Enzymatic Catalysis\nfor Formal Hydrophosphinylation of Alkenes"],"prefix":"10.1021","volume":"148","author":[{"given":"Duo","family":"Zhang","sequence":"first","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chentao","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangni","family":"Yin","sequence":"additional","affiliation":[{"name":"China University of Petroleum (East China) , , ,","place":["Qingdao, China, 266580"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juntao","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Duan","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8683-633X","authenticated-orcid":true,"given":"Lishuang","family":"Ma","sequence":"additional","affiliation":[{"name":"China University of Petroleum (East China) , , ,","place":["Qingdao, China, 266580"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhen","family":"Peng","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1765-9701","authenticated-orcid":true,"given":"Jian","family":"Xu","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310014"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"2026090312075237200_cit1","doi-asserted-by":"publisher","first-page":"6177","DOI":"10.1021\/cr030451c","article-title":"Synthetic methods for azaheterocyclic\nphosphonates and their biological activity","volume":"104","author":"Moonen","year":"2004","journal-title":"Chem. Rev."},{"key":"2026090312075237200_cit2","doi-asserted-by":"publisher","first-page":"4681","DOI":"10.1021\/cr040179m","article-title":"Organophosphorus\n\u03c0-conjugated materials","volume":"106","author":"Baumgartner","year":"2006","journal-title":"Chem. Rev."},{"key":"2026090312075237200_cit3","doi-asserted-by":"publisher","first-page":"4964","DOI":"10.1021\/jm2000085","article-title":"Design, synthesis, and X-ray crystallographic\nstudies of \u03b1-aryl substituted fosmidomycin analogues as inhibitors\nof Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase","volume":"54","author":"Andaloussi","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090312075237200_cit4","doi-asserted-by":"publisher","first-page":"8140","DOI":"10.1021\/jm501071f","article-title":"Structure-guided, single-point modifications in the phosphinic dipeptide\nstructure yield highly potent and selective inhibitors of neutral\naminopeptidases","volume":"57","author":"Vassiliou","year":"2014","journal-title":"J. Med. Chem."},{"key":"2026090312075237200_cit5","doi-asserted-by":"publisher","first-page":"7081","DOI":"10.1021\/acs.jmedchem.0c00407","article-title":"Phosphine\noxides from a medicinal\nchemist\u2019s perspective: physicochemical and in vitro parameters\nrelevant for drug discovery","volume":"63","author":"Finkbeiner","year":"2020","journal-title":"J. Med. Chem."},{"key":"2026090312075237200_cit6","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1126\/science.2434996","article-title":"Why nature\nchose phosphates","volume":"235","author":"Westheimer","year":"1987","journal-title":"Science"},{"key":"2026090312075237200_cit7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.cbpa.2018.09.018","article-title":"A role\nfor phosphorus redox in emerging and modern biochemistry","volume":"49","author":"Pasek","year":"2019","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2026090312075237200_cit8","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1146\/annurev.biochem.78.091707.100215","article-title":"Biosynthesis of phosphonic and phosphinic\nacid natural\nproducts","volume":"78","author":"Metcalf","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"2026090312075237200_cit9","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1016\/j.cbpa.2013.06.018","article-title":"Phosphonate\nbiosynthesis and catabolism: a treasure\ntrove of unusual enzymology","volume":"17","author":"Peck","year":"2013","journal-title":"Curr. Opin. Chem.\nBiol."},{"key":"2026090312075237200_cit10","doi-asserted-by":"publisher","first-page":"5704","DOI":"10.1021\/acs.chemrev.6b00536","article-title":"Phosphonate biochemistry","volume":"117","author":"Horsman","year":"2017","journal-title":"Chem.\nRev."},{"key":"2026090312075237200_cit11","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/335457a0","article-title":"Phosphonate biosynthesis:\nisolation of the enzyme responsible for the formation of a carbon-phosphorus\nbond","volume":"335","author":"Seidel","year":"1988","journal-title":"Nature"},{"key":"2026090312075237200_cit12","doi-asserted-by":"publisher","first-page":"5575","DOI":"10.1021\/ja00224a054","article-title":"Catalysis\nand thermodynamics of the phosphoenolpyruvate\/phosphopyruvate rearrangement.\nEntry into the phosphonate class of naturally occurring organophosphorus\ncompounds","volume":"110","author":"Bowman","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312075237200_cit13","doi-asserted-by":"publisher","first-page":"781","DOI":"10.7164\/antibiotics.45.781","article-title":"Studies on\nthe biosynthesis of bialaphos (SF-1293) 12. C\u2013P bond formation\nmechanism of bialaphos: discovery of a P-methylation enzyme","volume":"45","author":"Kamigiri","year":"1992","journal-title":"J. Antibiot."},{"key":"2026090312075237200_cit14","doi-asserted-by":"publisher","first-page":"8986","DOI":"10.1021\/bi201220r","article-title":"In vitro phosphinate\nmethylation by PhpK from Kitasatospora\nphosalacinea","volume":"50","author":"Werner","year":"2011","journal-title":"Biochemistry"},{"key":"2026090312075237200_cit15","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41929-019-0385-5","article-title":"Engineering new\ncatalytic activities in enzymes","volume":"3","author":"Chen","year":"2020","journal-title":"Nat. Catal."},{"key":"2026090312075237200_cit16","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.cbpa.2019.12.006","article-title":"Emerging strategies\nfor expanding the toolbox of enzymes\nin biocatalysis","volume":"55","author":"Sandoval","year":"2020","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2026090312075237200_cit17","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-021-00044-z","article-title":"Biocatalysis","volume":"1","author":"Bell","year":"2021","journal-title":"Nat. Rev. Methods Primers"},{"key":"2026090312075237200_cit18","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.1021\/acs.chemrev.5c00837","article-title":"Metalloenzyme-catalyzed radical reactions\nunknown or uncommon in native enzymology","volume":"126","author":"Fu","year":"2026","journal-title":"Chem.\nRev."},{"key":"2026090312075237200_cit19","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1126\/science.abj2830","article-title":"Directed evolution of nonheme iron\nenzymes to access abiological radical-relay C(sp3)\u2013H\nazidation","volume":"376","author":"Rui","year":"2022","journal-title":"Science"},{"key":"2026090312075237200_cit20","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41586-023-06822-x","article-title":"A light-driven\nenzymatic\nenantioselective radical acylation","volume":"625","author":"Xu","year":"2024","journal-title":"Nature"},{"key":"2026090312075237200_cit21","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1021\/acs.accounts.1c00719","article-title":"Photobiocatalysis\nfor abiological\ntransformations","volume":"55","author":"Harrison","year":"2022","journal-title":"Acc. Chem. Res."},{"key":"2026090312075237200_cit22","doi-asserted-by":"publisher","first-page":"5459","DOI":"10.1021\/acs.chemrev.2c00767","article-title":"Photobiocatalytic\nstrategies for organic synthesis","volume":"123","author":"Emmanuel","year":"2023","journal-title":"Chem. Rev."},{"key":"2026090312075237200_cit23","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1021\/acs.accounts.4c00129","article-title":"From ground-state\nto excited-state activation modes:\nFlavin-dependent \u201cene\u201d-reductases catalyzed non-natural\nradical reactions","volume":"57","author":"Fu","year":"2024","journal-title":"Acc. Chem. Res."},{"key":"2026090312075237200_cit24","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1126\/science.aaw1143","article-title":"Photoexcitation\nof flavoenzymes enables a stereoselective\nradical cyclization","volume":"364","author":"Biegasiewicz","year":"2019","journal-title":"Science"},{"key":"2026090312075237200_cit25","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41586-020-2406-6","article-title":"Photoenzymatic enantioselective\nintermolecular radical hydroalkylation","volume":"584","author":"Huang","year":"2020","journal-title":"Nature"},{"key":"2026090312075237200_cit26","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1038\/s41557-024-01494-0","article-title":"Stereodivergent photobiocatalytic\nradical cyclization through the repurposing and directed evolution\nof fatty acid photodecarboxylases","volume":"16","author":"Ju","year":"2024","journal-title":"Nat. Chem."},{"key":"2026090312075237200_cit27","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202412862","article-title":"Catalytic promiscuity\nof fatty acid photodecarboxylase enables stereoselective synthesis\nof chiral \u03b1-tetralones","volume":"63","author":"Xu","year":"2024","journal-title":"Angew. Chem.,\nInt. Ed."},{"key":"2026090312075237200_cit28","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1038\/s41929-025-01434-2","article-title":"Atom-economic enantioselective photoenzymatic radical hydroalkylation\nvia single-electron oxidation of carbanions","volume":"8","author":"Zhu","year":"2025","journal-title":"Nat. Catal."},{"key":"2026090312075237200_cit29","doi-asserted-by":"publisher","first-page":"44529","DOI":"10.1021\/jacs.5c17564","article-title":"Photoenzymatic C(sp3)\u2013H\nfunctionalization of 1,3-dicarbonyls enables enantioselective hydroalkylation\nof styrenes","volume":"147","author":"Wang","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312075237200_cit30","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202311762","article-title":"Photoenzymatic enantioselective\nsynthesis\nof oxygen-containing benzo-fused heterocycles","volume":"62","author":"Zhu","year":"2023","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312075237200_cit31","doi-asserted-by":"publisher","first-page":"18618","DOI":"10.1021\/jacs.5c00761","article-title":"Asymmetric enantio-complementary synthesis of thioethers\nvia ene-reductase-catalyzed C\u2013C bond formation","volume":"147","author":"Heckmann","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312075237200_cit32","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41557-024-01671-1","article-title":"Unmasking the reverse catalytic activity of \u2018ene\u2019-reductases\nfor asymmetric carbonyl desaturation","volume":"17","author":"Wang","year":"2025","journal-title":"Nat. Chem."},{"key":"2026090312075237200_cit33","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1038\/s44160-024-00596-4","article-title":"Biocatalytic desymmetrization for\nsynthesis of chiral enones using flavoenzymes","volume":"3","author":"Zeng","year":"2024","journal-title":"Nat. Synth."},{"key":"2026090312075237200_cit34","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/s41557-022-01083-z","article-title":"Using enzymes to tame nitrogen-centred radicals for\nenantioselective hydroamination","volume":"15","author":"Ye","year":"2023","journal-title":"Nat. Chem."},{"key":"2026090312075237200_cit35","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/s41929-023-00994-5","article-title":"Photoenzymatic\nenantioselective\nintermolecular radical hydroamination","volume":"6","author":"Zhang","year":"2023","journal-title":"Nat.\nCatal."},{"key":"2026090312075237200_cit36","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202218140","article-title":"Photoenzymatic hydrosulfonylation for the stereoselective synthesis\nof chiral sulfones","volume":"62","author":"Chen","year":"2023","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312075237200_cit37","doi-asserted-by":"publisher","first-page":"2748","DOI":"10.1021\/jacs.3c12513","article-title":"Single-electron\noxidation-initiated\nenantioselective hydrosulfonylation of olefins enabled by photoenzymatic\ncatalysis","volume":"146","author":"Shi","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312075237200_cit38","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1038\/s41929-025-01372-z","article-title":"Steering oxygen-centred\nradicals with ground-state ene-reductases for enantioselective intermolecular\nhydroalkoxylations","volume":"8","author":"Chen","year":"2025","journal-title":"Nat. Catal."},{"key":"2026090312075237200_cit39","doi-asserted-by":"publisher","first-page":"3367","DOI":"10.1021\/ja00904a013","article-title":"The photochemistry\nof riboflavin. I. The hydrogen transfer process in the anaerobic photobleaching\nof flavins","volume":"85","author":"Moore","year":"1963","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312075237200_cit40","doi-asserted-by":"publisher","first-page":"9622","DOI":"10.1021\/jacs.1c04334","article-title":"Ground-state\nelectron transfer as an initiation mechanism for biocatalytic C\u2013C\nbond forming reactions","volume":"143","author":"Fu","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312075237200_cit41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56437-1","article-title":"Ground-state flavin-dependent\nenzymes catalyzed enantioselective\nradical trifluoromethylation","volume":"16","author":"Duan","year":"2025","journal-title":"Nat. Commun."},{"key":"2026090312075237200_cit42","doi-asserted-by":"publisher","first-page":"12783","DOI":"10.1021\/acs.joc.1c01413","article-title":"Phosphine\noxides (\u2212POMe2) for medicinal chemistry: synthesis,\nproperties, and applications","volume":"86","author":"Stambirskyi","year":"2021","journal-title":"J. Org. Chem."},{"key":"2026090312075237200_cit43","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1021\/acs.jpcc.7b11299","article-title":"P = O moiety\nas an ambidextrous hydrogen bond acceptor","volume":"122","author":"Tupikina","year":"2018","journal-title":"J.\nPhys. Chem. C"},{"key":"2026090312075237200_cit44","doi-asserted-by":"publisher","first-page":"4948","DOI":"10.1021\/acs.jmedchem.6b00306","article-title":"Discovery\nof Brigatinib (AP26113), a phosphine oxide-containing, potent, orally\nactive inhibitor of anaplastic lymphoma kinase","volume":"59","author":"Huang","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026090312075237200_cit45","doi-asserted-by":"crossref","unstructured":"Mou, K.; Tian, Z.; Xu, W.; Kang, X.; Wang, Z.; Ding, B.; Wu, Q.\n          Photoenzymatic\nStereodivergent Hydrophosphinylation to Access Diverse P-Chirogenic\nand P-\/C-Bichirogenic Phosphorus Compounds\n          ChemRxiv\n          2025\n          10.26434\/chemrxiv-2025-ssqg9.","DOI":"10.26434\/chemrxiv-2025-ssqg9"},{"key":"2026090312075237200_cit46","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1021\/acs.orglett.4c00234","article-title":"Synthesis of \u03b3-oxo-phosphonates\nvia N-heterocyclic carbene-catalyzed acylphosphorylation of alkenes","volume":"26","author":"Mo","year":"2024","journal-title":"Org. Lett."},{"key":"2026090312075237200_cit47","doi-asserted-by":"publisher","first-page":"7934","DOI":"10.1021\/jacs.9b02709","article-title":"Stereodivergent\nprotein engineering of a lipase to access all possible stereoisomers\nof chiral esters with two stereocenters","volume":"141","author":"Xu","year":"2019","journal-title":"J.\nAm. Chem. Soc."},{"key":"2026090312075237200_cit48","doi-asserted-by":"publisher","first-page":"13204","DOI":"10.1002\/anie.201901491","article-title":"The crucial\nrole of methodology development in directed evolution of selective\nenzymes","volume":"59","author":"Qu","year":"2020","journal-title":"Angew. Chem., Int. Ed."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c08848","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/34\/36842\/66947034\/jacs.6c08848.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/34\/36842\/66947034\/jacs.6c08848.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T16:22:54Z","timestamp":1788452574000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/34\/36842\/5282465\/Ground-State-Flavin-Dependent-Enzymatic-Catalysis"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":48,"journal-issue":{"issue":"34","published-online":{"date-parts":[[2026,8,20]]},"published-print":{"date-parts":[[2026,9,2]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c08848","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]}}}