Optimization of central carbon metabolism by Warburg effect of human cancer cell improves triterpenes biosynthesis in yeast

Optimization of central carbon metabolism (CCM) represents an attractive but also very challenging strategy to improve the biosynthesis of valuable chemicals due to the complex regulation of the CCM in yeast. In this study, we triggered the similar Warburg effect of cancer cells in yeast strains by introducing the human hypoxia-inducible factor-1 (HIF-1) complex, which regulated the expression of numerous enzymes involved in CCM and redirected the metabolic flux from glycolysis to tricarboxylic acid cycle. This redirection promoted the production of squalene to a 2.7-fold increase than the control strain BY4741. Furthermore, the HIF-1 complex boosted the production of represented endogenous triterpenoid ergosterol to 1145.95 mg/L, and exogenous triterpenoid lupeol to 236.35 mg/L in shake flask cultivation, 10.5-fold and 9.2-fold increase than engineered strains without HIF-1 complex integration, respectively. This study provides a novel strategy for optimizing CCM by HIF-1 mediated Warburg effect of cancer cells to improve biosynthesis of triterpenoids in yeast.