Metabolic engineering of Saccharomyces cerevisiae for production of spermidine under optimal culture conditions

Spermidine is a polyamine compound exhibiting important biological activities, such as increasing lifespan, inflammation reduction, and plant growth control. As such, many applications of spermidine as a bio-modulating agent are anticipated. However, sustainable and scalable production of spermidine has not been achieved yet. Therefore, construction of a spermidine production system using Saccharomyces cerevisiae was attempted in this study. In order to secrete spermidine into fermentation broth, TPO1 coding for the polyamine transporter was overexpressed in an engineered S. cerevisiae strain capable of accumulating high concentrations of spermidine. Through optimization of fermentation conditions, the resulting strain (OS123/pTPO1) produced 63.6 mg/l spermidine with a yield of 1.3 mg spermidine/g glucose. However, we observed that spermidine production was repressed in the presence of glucose. To circumvent this problem, the genetic modifications for overproducing spermidine were introduced into an engineered S. cerevisiae capable of fermenting xylose. In a fed-batch fermentation using a mixture of glucose and xylose, the resulting strain (SR8 OS123/pTPO1) produced 224 mg/l spermidine with a yield of 2.2 mg spermidine/g sugars. These results suggest that engineered yeast constructed in this study can be employed for the production of spermidine.