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Engineering the yeast Saccharomyces cerevisiae for the production of L-(+)-ergothioneine

View ORCID ProfileSteven A. van der Hoek, Behrooz Darbani, Karolina E. Zugaj, Bala Krishna Prabhala, Mathias Bernfried Biron, Milica Randelovic, Jacqueline B. Medina, Douglas B. Kell, Irina Borodina
doi: https://doi.org/10.1101/667592
Steven A. van der Hoek
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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  • ORCID record for Steven A. van der Hoek
Behrooz Darbani
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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Karolina E. Zugaj
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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Bala Krishna Prabhala
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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Mathias Bernfried Biron
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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Milica Randelovic
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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Jacqueline B. Medina
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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Douglas B. Kell
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
2Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK
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  • For correspondence: irbo@biosustain.dtu.dk doukel@biosustain.dtu.dk
Irina Borodina
1The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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  • For correspondence: irbo@biosustain.dtu.dk doukel@biosustain.dtu.dk
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Abstract

L-(+)-Ergothioneine is an unusual, naturally occurring antioxidant nutraceutical that has been shown to help reduce cellular oxidative damage. Humans do not biosynthesise it, so can acquire it only from their diet; it exploits a specific transporter (SLC22A4) for its uptake. ERG is considered to be a nutraceutical and possible vitamin that is involved in the maintenance of health, and seems to be at too low a concentration in several diseases in vivo. Ergothioneine is thus a potentially useful dietary supplement. Present methods of commercial production rely on extraction from natural sources or on chemical synthesis. Here we describe the engineering of the baker’s yeast Saccharomyces cerevisiae to produce ergothioneine by fermentation in defined media. After integrating combinations of ERG biosynthetic pathways from different organisms, we screened yeast strains for their production of ERG. The highest-producing strain was also engineered with known ergothioneine transporters. The effect of amino acid supplementation of the medium was investigated and the nitrogen metabolism of S. cerevisiae was altered by knock-out of TOR1 or YIH1. We also optimized the media composition using fractional factorial methods. Our optimal strategy led to a titer of 598 ± 18 mg/L ergothioneine in fed-batch culture in bioreactors. Because S. cerevisiae is a GRAS (‘generally recognised as safe’) organism that is widely used for nutraceutical production, this work provides a promising process for the biosynthetic production of ERG.

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Posted June 12, 2019.
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Engineering the yeast Saccharomyces cerevisiae for the production of L-(+)-ergothioneine
Steven A. van der Hoek, Behrooz Darbani, Karolina E. Zugaj, Bala Krishna Prabhala, Mathias Bernfried Biron, Milica Randelovic, Jacqueline B. Medina, Douglas B. Kell, Irina Borodina
bioRxiv 667592; doi: https://doi.org/10.1101/667592
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Engineering the yeast Saccharomyces cerevisiae for the production of L-(+)-ergothioneine
Steven A. van der Hoek, Behrooz Darbani, Karolina E. Zugaj, Bala Krishna Prabhala, Mathias Bernfried Biron, Milica Randelovic, Jacqueline B. Medina, Douglas B. Kell, Irina Borodina
bioRxiv 667592; doi: https://doi.org/10.1101/667592

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