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Inactivation of Flavoenzyme-Encoding Gene flsO1 in Fluostatin Biosynthesis Leads to Diversified Angucyclinone Derivatives

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journal contribution
posted on 03.02.2021, 21:29 by Chunfang Yang, Chunshuai Huang, Chunyan Fang, Liping Zhang, Siqiang Chen, Qingbo Zhang, Changsheng Zhang, Wenjun Zhang
Inactivation of the flavoenzyme-encoding gene flsO1 in fluostatin biosynthesis led to the isolation of four new angucyclinone derivatives (11, 12, 14, and 15), among which fluostarenes A (14) and B (15) featured the unprecedented 6/6/5/6/6 pentacyclic skeleton with fusion of a benzo­[b]­fluorene and a six-membered lactone ring. Both 14 and 15 were putatively generated via quinone methide-mediated nonenzymatic reactions. Fluostarene B (15) exhibited cytotoxicity against several cancer cell lines with IC50 values ranging from 7 to 10 μM. Fluostarenes A (14), B (15), and PK1 (16) showed α-glucosidase inhibition activity with IC50 of 0.89, 1.58, and 0.13 μM, respectively. Successful complementation of the ΔflsO1 mutant with alpK from kinamycin biosynthesis suggests that FlsO1 should function equivalently to AlpK as a putative C-5 hydroxylase.