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Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli

Author

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  • Akira Nakagawa

    (Applied Microbiology laboratory, Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University)

  • Eitaro Matsumura

    (Applied Microbiology laboratory, Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University)

  • Takashi Koyanagi

    (Applied Microbiology laboratory, Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University)

  • Takane Katayama

    (Graduate School of Biostudies, Kyoto University, Oiwake-cho, Kitashirakawa)

  • Noriaki Kawano

    (Breeding and Physiology Laboratory, Tsukuba Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition)

  • Kayo Yoshimatsu

    (Breeding and Physiology Laboratory, Tsukuba Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition)

  • Kenji Yamamoto

    (Applied Microbiology laboratory, Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University)

  • Hidehiko Kumagai

    (Applied Microbiology laboratory, Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University)

  • Fumihiko Sato

    (Graduate School of Biostudies, Kyoto University, Oiwake-cho, Kitashirakawa)

  • Hiromichi Minami

    (Applied Microbiology laboratory, Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University)

Abstract

Opiates such as morphine and codeine are mainly obtained by extraction from opium poppies. Fermentative opiate production in microbes has also been investigated, and complete biosynthesis of opiates from a simple carbon source has recently been accomplished in yeast. Here we demonstrate that Escherichia coli serves as an efficient, robust and flexible platform for total opiate synthesis. Thebaine, the most important raw material in opioid preparations, is produced by stepwise culture of four engineered strains at yields of 2.1 mg l−1 from glycerol, corresponding to a 300-fold increase from recently developed yeast systems. This improvement is presumably due to strong activity of enzymes related to thebaine synthesis from (R)-reticuline in E. coli. Furthermore, by adding two genes to the thebaine production system, we demonstrate the biosynthesis of hydrocodone, a clinically important opioid. Improvements in opiate production in this E. coli system represent a major step towards the development of alternative opiate production systems.

Suggested Citation

  • Akira Nakagawa & Eitaro Matsumura & Takashi Koyanagi & Takane Katayama & Noriaki Kawano & Kayo Yoshimatsu & Kenji Yamamoto & Hidehiko Kumagai & Fumihiko Sato & Hiromichi Minami, 2016. "Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli," Nature Communications, Nature, vol. 7(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10390
    DOI: 10.1038/ncomms10390
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    Cited by:

    1. Yu Wang & Fabiana Subrizi & Eve M. Carter & Tom D. Sheppard & John M. Ward & Helen C. Hailes, 2022. "Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Leixia Chu & Xiaoxia Luo & Taoting Zhu & Yingying Cao & Lili Zhang & Zixin Deng & Jiangtao Gao, 2022. "Harnessing phosphonate antibiotics argolaphos biosynthesis enables a synthetic biology-based green synthesis of glyphosate," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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