title: Glucose-based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae.
abstract: 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.
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Germann
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Simo A
authors.initials: SA
authors.lastname: Baallal Jacobsen
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Schneider
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Harrison
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Niels B
authors.initials: NB
authors.lastname: Jensen
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Steen G
authors.initials: SG
authors.lastname: Stahlhut
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Irina
authors.initials: I
authors.lastname: Borodina
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Hao
authors.initials: H
authors.lastname: Luo
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Jiangfeng
authors.initials: J
authors.lastname: Zhu
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Maury
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark. jfor@biosustain.dtu.dk.
authors.forename: Jochen
authors.initials: J
authors.lastname: Forster
mesh_terms: D000818:Animals; D061249:Batch Cell Culture Techniques; D053898:Biosynthetic Pathways; D003470:Culture Media / Q000737:chemistry; D005285:Fermentation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007218:Industrial Microbiology / Q000379:methods; D008550:Melatonin / Q000096:biosynthesis*; D060847:Metabolic Engineering / Q000379:methods*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics* / Q000254:growth & development*; D012701:Serotonin / Q000031:analogs & derivatives / Q000096:biosynthesis
chemical_list: D003470:Culture Media; D012701:Serotonin; D005947:Glucose; D008550:Melatonin; C006389:N-acetylserotonin
keywords: EasyClone vectors; Melatonin; Microbial production; Saccharomyces cerevisiae; Serotonin