Systems Metabolic Engineering of Saccharomyces cerevisiae for the High-Level Production of (2S)-Eriodictyol

Abstract

(2S)-eriodictyol (ERD) is a flavonoid widely found in citrus fruits, vegetables, and important medicinal plants with neuroprotective, cardioprotective, antidiabetic, and anti-obesity effects. However, the microbial synthesis of ERD is limited by complex metabolic pathways and often results in a low production performance. Here, we engineered Saccharomyces cerevisiae by fine-tuning the metabolism of the ERD synthesis pathway. The results showed that the ERD titer was effectively increased, and the intermediate metabolites levels were reduced. First, we successfully reconstructed the de novo synthesis pathway of p-coumaric acid in S. cerevisiae and fine-tuned the metabolic pathway using promoter engineering and terminator engineering for the high-level production of (2S)-naringenin. Subsequently, the synthesis of ERD was achieved by introducing the ThF3′H gene from Tricyrtis hirta. Finally, by multiplying the copy number of the ThF3′H gene, the production of ERD was further increased, reaching 132.08 mg L−1. Our work emphasizes the importance of regulating the metabolic balance to produce natural products in microbial cell factories.