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A severe leakage of intermediates to shunt products in acarbose biosynthesis

Author

Listed:
  • Qinqin Zhao

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Yuchang Luo

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Xin Zhang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Qianjin Kang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Dan Zhang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Lili Zhang

    (Tarim University)

  • Linquan Bai

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Tarim University)

  • Zixin Deng

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

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.

Suggested Citation

  • Qinqin Zhao & Yuchang Luo & Xin Zhang & Qianjin Kang & Dan Zhang & Lili Zhang & Linquan Bai & Zixin Deng, 2020. "A severe leakage of intermediates to shunt products in acarbose biosynthesis," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15234-8
    DOI: 10.1038/s41467-020-15234-8
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    Cited by:

    1. Takeshi Tsunoda & Arash Samadi & Sachin Burade & Taifo Mahmud, 2022. "Complete biosynthetic pathway to the antidiabetic drug acarbose," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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