A severe leakage of intermediates to shunt products in acarbose biosynthesis

Qinqin Zhao, Yuchang Luo, Xin Zhang, Qianjin Kang, Dan Zhang, Lili Zhang, Linquan Bai () and Zixin Deng
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Qinqin Zhao: Shanghai Jiao Tong University
Yuchang Luo: Shanghai Jiao Tong University
Xin Zhang: Shanghai Jiao Tong University
Qianjin Kang: Shanghai Jiao Tong University
Dan Zhang: Shanghai Jiao Tong University
Lili Zhang: Tarim University
Linquan Bai: Shanghai Jiao Tong University
Zixin Deng: Shanghai Jiao Tong University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The α-glucosidase inhibitor acarbose, produced by Actinoplanes sp. SE50/110, is a well-known drug for the treatment of type 2 diabetes mellitus. However, the largely unexplored biosynthetic mechanism of this compound has impeded further titer improvement. Herein, we uncover that 1-epi-valienol and valienol, accumulated in the fermentation broth at a strikingly high molar ratio to acarbose, are shunt products that are not directly involved in acarbose biosynthesis. Additionally, we find that inefficient biosynthesis of the amino-deoxyhexose moiety plays a role in the formation of these shunt products. Therefore, strategies to minimize the flux to the shunt products and to maximize the supply of the amino-deoxyhexose moiety are implemented, which increase the acarbose titer by 1.2-fold to 7.4 g L−1. This work provides insights into the biosynthesis of the C7-cyclitol moiety and highlights the importance of assessing shunt product accumulation when seeking to improve the titer of microbial pharmaceutical products.

Date: 2020
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DOI: 10.1038/s41467-020-15234-8

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