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Cooperative Redox Reactions Encoded by Two Gene Clusters Enable Intermolecular Cycloaddition Cascade for the Formation of Meroaspochalasins
Author(s) -
Li Pengkun,
Meng Jie,
Zhang Xiaotian,
Zhang Xiaopeng,
Ye Yonghao,
Zhao Yunpeng,
Huang Xuenian,
Zha Ziou,
Guan Zhenhua,
Lai Suitian,
Chen Zhe,
Luo Zengwei,
Wang Jianping,
Chen Chunmei,
Liu Junjun,
Gu Lianghu,
Sun Yuhui,
Li Shuming,
Zhu Hucheng,
Ye Ying,
Zhou Yuan,
Zhang Yonghui
Publication year - 2025
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202502766
Subject(s) - intermolecular force , cycloaddition , redox , chemistry , cascade , combinatorial chemistry , photochemistry , molecule , organic chemistry , catalysis , chromatography
Abstract Meroaspochalasins (mAPOs) are a group of intricate heteromers comprising two distinct subunits, dienophile aspochalasin, and diene isobenzofuran, of which the biosynthetic mechanism is of great interest yet unrevealed. In this study, two independent biosynthetic gene clusters (BGCs), flas and epi , being responsible for the biosynthesis of aspochalasin B ( 7 ) and pre‐diene hemiacetal 21 (or 26 ), respectively, were identified in the filamentous fungus Aspergillus flavipes . In vivo and in vitro studies proved that a flavin adenine dinucleotide (FAD)‐dependent oxidase FlasF in the flas cluster catalyzes the crucial oxidation to generate diverse aspochalasin monomers, particularly the dienophile 7 . Interactive reduction catalyzed by the short‐chain alcohol dehydrogenase/reductase (SDR) FlasG and endogenous NADPH further increases the complexity of this anabolic network. The cytochrome P450 enzyme EpiC and SDR enzyme EpiD in the epi cluster collaboratively catalyze the formation of pre‐diene 21 (or 26 ), which can spontaneously dehydrate to yield a diene, leading to the nonenzymatic cascade of [4 π + 2 π ] Diels–Alder and formal [5 π + 2π] cycloaddition reaction to generate mAPO dimers and trimer progressively. Moreover, the FAD‐dependent oxidase EpiG catalyzes the hydroxylation at the C3 position of the diene as a critical step in the formation of mAPO trimers.