Synergistic Glycerol Coutilization Promotes Metabolic Fitness of Saccharomyces cerevisiae on Lactate

Wet waste-derived lactic acid is a promising alternative carbon source for yeast-based biorefineries, but the knowledge and demonstration of its utilization are lacking. Using 22 natural isolates of Saccharomyces cerevisiae and two non-conventional yeasts as the experimental model, here we show that there is huge inter- and intra-species variability among yeasts in terms of their lactate utilization capacity. Interestingly, in agreement with the underlying theoretical framework, glycerol cofeeding at a molar ratio of 0.1-0.5 is often necessary and sufficient to substantially improve the utilization efficiency in S. cerevisiae, i.e., up to 94% of its maximum theoretical yield relative to glucose. The synergistic effect of glycerol cofeeding is modulated by the precultivation medium--i.e., whether the cells were previously grown on glucose or acetate--and the glycerol/lactate molar ratio applied. Specifically, a higher molar ratio (up to 2.5) often leads to saturation or even antagonism. Using the knowledge of S. cerevisiae metabolism, potential mechanistic underpinnings of the observed phenomena are given to guide future metabolic engineering endeavors.