Glucose-based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae

Susanne Manuela Germann, Simo Abdessamad Jacobsen, Konstantin Schneider, Scott James Harrison, Niels Bjerg Jensen, Xiao Chen, Steen Gustav Stahlhut, Irina Borodina, Hao Luo, Jiangfeng Zhu, Jerome Maury, Jochen Förster

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Melatonin is a natural mammalian hormone that plays an important role in regulating the circadian cycle in humans. It is a clinically effective drug exhibiting positive effects as a sleep aid and a powerful antioxidant used as a dietary supplement. Commercial melatonin production is predominantly performed by complex chemical synthesis. In this study, we demonstrate microbial production of melatonin and related compounds, such as serotonin and N-acetylserotonin. We generated Saccharomyces cerevisiae strains that comprise heterologous genes encoding one or more variants of an L-tryptophan hydroxylase, a 5-hydroxy-L-tryptophan decarboxylase, a serotonin acetyltransferase, an acetylserotonin O-methyltransferase, and means for providing the cofactor tetrahydrobiopterin via heterologous biosynthesis and recycling pathways. We thereby achieved de novo melatonin biosynthesis from glucose. We furthermore accomplished increased product titers by altering expression levels of selected pathway enzymes and boosting co-factor supply. The final yeast strain produced melatonin at a titer of 14.50 ± 0.57 mg L−1 in a 76h fermentation using simulated fed-batch medium with glucose as sole carbon source. Our study lays the basis for further developing a yeast cell factory for biological production of melatonin.
Original languageEnglish
JournalBiotechnology Journal
Issue number5
Pages (from-to)717-724
Number of pages8
Publication statusPublished - 2016

Bibliographical note

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


  • Melatonin
  • Serotonin
  • Microbial production
  • EasyClone vectors
  • Saccharomyces cerevisiae

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