Developing Thermosensitive Metabolic Regulation Strategies in the Fermentation Process of <i>Saccharomyces cerevisiae</i> to Enhance α-Bisabolene Production

α-Bisabolene's distinctive aroma is highly prized in fragrances and cosmetics, while its antioxidant properties hold significant pharmaceutical potential. However, the production of α-bisabolene in <i>Saccharomyces cerevisiae</i> remains an outstanding challenge due to cell growth limitations and insufficient supply of the α-bisabolene precursor farnesyl pyrophosphate. In this work, a new <i>S. cerevisiae</i> platform strain capable of producing high levels of α-bisabolene was presented. Carbon flux in the α-bisabolene synthesis pathway was maximized by iterative enhancement of the mevalonate metabolic pathway. The effects of MVA pathway intermediates on cell growth were addressed through a two-stage fermentation controlled based on a temperature-sensitive regulation strategy. The fermentation medium was optimized based on metabolomics and response surface model analysis. Under the optimal fermentation process, the titer of α-bisabolene reached 18.6 g/L during fed-batch fermentation, representing the highest titer reported to date. These strategies open up new avenues for industrial-scale terpene biosynthesis.