<i>De Novo</i> Biosynthesis of a Bioactive\nMeroterpene Bakuchiol in Yeast

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