Inactivation of Flavoenzyme-Encoding Gene flsO1 in Fluostatin Biosynthesis Leads to Diversified Angucyclinone Derivatives
2021
Yang, Chunfang | Huang, Chunshuai | Fang, Chunyan | Zhang, Liping | Chen, Siqiang | Zhang, Qingbo | Zhang, Changsheng | Zhang, Wenjun
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.
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