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The formation of the aromatic core in the middle of the polyketide chain is unusual. We characterized a cytochrome\u2005P450 enzyme that can catalyze the hallmark benzene ring formation from an acyclic polyene substrate through genetic and biochemical analysis. Using this P450 as a beacon for genome mining, we obtained 12 homologous type I polyketide synthase (PKS) gene clusters, among which two gene clusters are activated and able to produce trialkyl\u2010substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the plausible mechanism for P450\u2010catalyzed benzene ring formation. Our work expands our knowledge of the catalytic diversity of cytochrome\u2005P450.<\/jats:p>","DOI":"10.1002\/anie.202214026","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T14:25:40Z","timestamp":1669991140000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Cytochrome\u2005P450 Catalyzes Benzene Ring Formation in the Biosynthesis of Trialkyl\u2010Substituted Aromatic Polyketides"],"prefix":"10.1002","volume":"62","author":[{"given":"Yu Meng","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology Institute of Functional Biomolecules Chemistry and Biomedicine Innovation Center (ChemBIC) School of Life Sciences Nanjing University  Nanjing 210023 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Er Juan","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of 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