Efficient biosynthesis of heterodimeric C3-aryl pyrroloindoline alkaloids

Wenya Tian, Chenghai Sun, Mei Zheng, Jeffrey R. Harmer, Mingjia Yu, Yanan Zhang, Haidong Peng, Dongqing Zhu, Zixin Deng, Shi-Lu Chen, Mehdi Mobli, Xinying Jia () and Xudong Qu ()
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Wenya Tian: Wuhan University
Chenghai Sun: Wuhan University
Mei Zheng: Wuhan University
Jeffrey R. Harmer: The University of Queensland
Mingjia Yu: Beijing Institute of Technology
Yanan Zhang: Wuhan University
Haidong Peng: Wuhan University
Dongqing Zhu: Wuhan University
Zixin Deng: Wuhan University
Shi-Lu Chen: Beijing Institute of Technology
Mehdi Mobli: The University of Queensland
Xinying Jia: The University of Queensland
Xudong Qu: Wuhan University

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract Many natural products contain the hexahydropyrrolo[2, 3-b]indole (HPI) framework. HPI containing chemicals exhibit various biological activities and distinguishable structural arrangement. This structural complexity renders chemical synthesis very challenging. Here, through investigating the biosynthesis of a naturally occurring C3-aryl HPI, naseseazine C (NAS-C), we identify a P450 enzyme (NascB) and reveal that NascB catalyzes a radical cascade reaction to form intramolecular and intermolecular carbon–carbon bonds with both regio- and stereo-specificity. Surprisingly, the limited freedom is allowed in specificity to generate four types of C3-aryl HPI scaffolds, and two of them were not previously observed. By incorporating NascB into an engineered strain of E. coli, we develop a whole-cell biocatalysis system for efficient production of NAS-C and 30 NAS analogs. Interestingly, we find that some of these analogs exhibit potent neuroprotective properties. Thus, our biocatalytic methodology offers an efficient and simple route to generate difficult HPI framework containing chemicals.

Date: 2018
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DOI: 10.1038/s41467-018-06528-z

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