(+)-Nootkatone is a valuable, functional sesquiterpene that is widely used in food, cosmetics, pharmaceutical, agriculture, and other fields. However, only traces of it accumulate in plants, which is insufficient to meet the market demand. Therefore, commercial (+)-nootkatone is currently synthesized from (+)-valencene. Here, we engineered Saccharomyces cerevisiae to achieve high production of (+)-valencene. Employing gene screening, protein engineering and biosynthetic pathway optimization, we achieved 12.4 g/L (+)-valencene production with the mutant strain. This titer was further increased to 16.6 g/L, the highest titer reported to date, by coupling critical factors for cell growth and biochemical pathway induction. Subsequently, (+)-nootkatone was chemically synthesized from bio-fermented (+)-valencene with a yield of 80%. This study achieved efficient microbial synthesis of (+)-valencene, which may be utilized in industrial production and stabilize the supply of (+)-nootkatone.

(+)-Nootkatone 是一种有价值的功能性倍半萜，广泛应用于食品、化妆品、医药、农业等领域。但在植物体内仅积累微量，不足以满足市场需求。因此，商业上的 (+)-nootkatone 目前是由 (+)-valencene 合成的。在这里，我们设计了酿酒酵母以实现(+)-瓦伦烯的高产量。通过基因筛选、蛋白质工程和生物合成途径优化，我们用突变菌株实现了 12.4 g/L (+)-瓦伦烯的产量。通过耦合细胞生长和生化途径诱导的关键因素，该滴度进一步增加到 16.6 g/L，这是迄今为止报道的最高滴度。随后，由生物发酵的(+)-瓦伦烯化学合成(+)-nootkatone，产率为80%。该研究实现了(+)-瓦伦烯的高效微生物合成，可用于工业生产并稳定(+)-nootkatone的供应。