Engineering the Yeast <i>Saccharomyces</i> <i>cerevisiae</i> for the Production of L-(+)-Ergothioneine

van der Hoek, Steven A, Darbani, Behrooz, Zugaj, Karolina E, Prabhala, Bala Krishna, Biron, Mathias Bernfried, Randelovic, Milica, Medina, Jacqueline B, Kell, Douglas B ORCID: 0000-0001-5838-7963 and Borodina, Irina
(2019) Engineering the Yeast <i>Saccharomyces</i> <i>cerevisiae</i> for the Production of L-(+)-Ergothioneine. FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY, 7. 262-.

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L-(+)-Ergothioneine (ERG) is an unusual, naturally occurring antioxidant nutraceutical that has been shown to help reduce cellular oxidative damage. Humans do not biosynthesise ERG, but acquire it 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 <i>in vivo</i>. 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 <i>Saccharomyces cerevisiae</i> 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 <i>S. cerevisiae</i> was altered by knock-out of <i>TOR</i>1 or <i>YIH</i>1. 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 1 L bioreactors. Because <i>S. cerevisiae</i> is a GRAS ("generally recognized as safe") organism that is widely used for nutraceutical production, this work provides a promising process for the biosynthetic production of ERG.

Item Type: Article
Uncontrolled Keywords: ergothioneine, metabolic engineering, medium optimization, Saccharomyces cerevisiae, yeast, nutraceutical
Depositing User: Symplectic Admin
Date Deposited: 28 Nov 2019 14:43
Last Modified: 19 Oct 2023 06:01
DOI: 10.3389/fbioe.2019.00262
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