Combination of microbial and chemical synthesis for the sustainable production of β‐elemene, a promising plant‐extracted anticancer compound

Beta‐elemene, a class of sesquiterpene derived from the Chinese medicinal herb Curcuma wenyujin, is widely used in clinical medicine due to its broad‐spectrum antitumor activity. However, the unsustainable plant extraction prompted the search for environmentally friendly strategies for β‐elemene production. In this study, we designed a Yarrowia lipolytica cell factory that can continuously produce germacrene A, which is further converted into β‐elemene with 100% yield through a Cope rearrangement reaction by shifting the temperature to 250°C. First, the productivity of four plant‐derived germacrene A synthases was evaluated. After that, the metabolic flux of the precursor to germacrene A was maximized by optimizing the endogenous mevalonate pathway, inhibiting the competing squalene pathway, and expressing germacrene A synthase gene in multiple copies. Finally, the most promising strain achieved the highest β‐elemene titer reported to date with 5.08 g/L. This sustainable and green method has the potential for industrial β‐elemene production. Microbial reactions with a simple thermally‐induced transformation as an alternative to plant extraction for the sustainable production of anticancer compound β‐elemene. The “push‐pull‐restrain” strategy directs the carbon flux to the metabolic reaction of the target products without disturbing the endogenous metabolic balance.