De Novo Biosynthesis of Caffeic Acid from Glucose by Engineered Saccharomyces cerevisiae

Caffeic acid is a plant phenolic compound possessing extensive pharmacological activities. Here, we identified that p-coumaric acid 3-hydroxylase from Arabidopsis thaliana was capable of hydroxylating p-coumaric acid to form caffeic acid in Saccharomyces cerevisiae. Then, we introduced a combined caffeic acid biosynthetic pathway into S. cerevisiae and obtained 0.183 mg L^-1 caffeic acid from glucose. Next we improved the tyrosine biosynthesis in S. cerevisiae by blocking the pathway flux to aromatic alcohols and eliminating the tyrosine-induced feedback inhibition resulting in caffeic acid production of 2.780 mg L^-1. Finally, the medium was optimized, and the highest caffeic acid production obtained was 11.432 mg L^-1 in YPD medium containing 4% glucose. This study opens a route to produce caffeic acid from glucose in S. cerevisiae and establishes a platform for the biosynthesis of caffeic acid derived metabolites.