Cooperative Redox Reactions Encoded by Two Gene Clusters Enable Intermolecular Cycloaddition Cascade for the Formation of Meroaspochalasins
Abstract
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.
Article Details
Authors (22)
Pengkun Li
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
Jie Meng
Hefei National Research Center for Physical Sciences at the Microscale and Synergetic Innovation Center of Quantum Information & Quantum Physics, New Cornerstone Science Laboratory
Xiaotian Zhang
Xiaopeng Zhang
Institute for Materials Chemistry and Engineering and IRCCS, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
Yonghao Ye
Yunpeng Zhao
Xuenian Huang
Shandong Provincial Key Laboratory of Synthetic Biology, Key Laboratory of Biofuels Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences Qingdao 266101 China
Ziou Zha
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
Zhenhua Guan
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
Suitian Lai
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
Zhe Chen
Gladstone Institutes, San Francisco, CA, USA.
Zengwei Luo
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
Jianping Wang
Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering
Chunmei Chen
Junjun Liu
Techshake Biotechnology Co., Ltd., Xi’an, Shaanxi, China.
Lianghu Gu
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
Yuhui Sun
Shuming Li
Hucheng Zhu
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
Ying Ye
Yuan Zhou
State Key Laboratory of Cognitive Science and Mental Health, Institute of Psychology, Chinese Academy of Sciences
Yonghui Zhang