De Novo Biosynthesis of a Bioactive Meroterpene Bakuchiol in Yeast.

Bakuchiol (BAK), a specialized meroterpene, is known for its valuable biological properties and has recently gained prominence in cosmetology for its retinol-like functionality. However, low abundance in natural sources leads to environmentally unfriendly and unsustainable practices associated with crop-based manufacturing and chemical synthesis. Here, we identified a prenyltransferase (PT) from Psoralea corylifolia that catalyzes the reverse geranylation of a nonaromatic carbon in para-coumaric acid (p-CA), coupled with a decarboxylation step to form BAK. Given that the biosynthesis pathway of BAK is well elucidated, we engineered Saccharomyces cerevisiae to produce BAK, starting from glucose. To enhance the titer of BAK, we employed a multifaceted approach that included increasing the supply of precursors, balancing the fluxes in the two parallel biosynthetic pathways, engineering of prenyltransferase, and fusing enzymes. Consequently, the engineered yeast strains showed a marked improvement of 117.3-fold in BAK production, reaching a titer of 9.28 mg/L from glucose. Our work provides a viable approach for the sustainable microbial production of complex natural meroterpenes.