Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli

• Published in: Nature communications 2016-02, Vol.7 (1), p.10390-10390, Article 10390
• Main Authors: Nakagawa, Akira, Matsumura, Eitaro, Koyanagi, Takashi, Katayama, Takane, Kawano, Noriaki, Yoshimatsu, Kayo, Yamamoto, Kenji, Kumagai, Hidehiko, Sato, Fumihiko, Minami, Hiromichi
• Format: Article
• Language: English
• Subjects: 14; 38/22; 38/77; 631/326/41/2537; 631/61/338; 631/92/60; 82/58; 82/80; Acetyltransferases - genetics; Analgesics, Opioid - metabolism; Benzylisoquinolines - metabolism; Codeine - biosynthesis; Coptis - genetics; Escherichia coli - genetics; Escherichia coli - metabolism; Fermentation; Glycerol - metabolism; Humanities and Social Sciences; Hydrocodone - metabolism; Methyltransferases - genetics; Methyltransferases - metabolism; Morphine - biosynthesis; multidisciplinary; Organisms, Genetically Modified - genetics; Organisms, Genetically Modified - metabolism; Oxidoreductases - genetics; Oxycodone - metabolism; Papaver - genetics; Science; Science (multidisciplinary); Thebaine - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10390

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. Opiates—the gold standard for pain relief—are currently produced by extraction from opium poppies. Here the authors show that bacteria can serve as an efficient and flexible platform for the production of opiates by demonstrating the total synthesis of Thebaine and hydrocodone from stepwise fermentation in E. coli .