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Glucose‐based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae
Author(s) -
Germann Susanne M.,
Baallal Jacobsen Simo A.,
Schneider Konstantin,
Harrison Scott J.,
Jensen Niels B.,
Chen Xiao,
Stahlhut Steen G.,
Borodina Irina,
Luo Hao,
Zhu Jiangfeng,
Maury Jérôme,
Forster Jochen
Publication year - 2016
Publication title -
biotechnology journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.144
H-Index - 84
eISSN - 1860-7314
pISSN - 1860-6768
DOI - 10.1002/biot.201500143
Subject(s) - melatonin , biochemistry , saccharomyces cerevisiae , yeast , biology , fermentation , heterologous , tetrahydrobiopterin , enzyme , cofactor , endocrinology , gene
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.