Engineering a modular yeast platform integrating xylose metabolism and plant polyphenol biosynthesis

Polyphenols are plant-derived secondary metabolites with significant pharmaceutical potential, including flavonoids and stilbenoids. Microbial production of these compounds offers a sustainable alternative to plant extraction and chemical synthesis. However, most studies rely on glucose as a sole carbon source, limiting the use of lignocellulosic biomass, a sustainable and economical resource for biomanufacturing. Here, we present an engineering approach to develop a xylose-utilizing Saccharomyces cerevisiae platform that integrates carbon assimilation with plant polyphenol biosynthesis. We designed and optimized a naringenin biosynthetic module through heterologous gene screening, expression balancing, and culture optimization, achieving a 42-fold improvement (54.7 mg/L in XN03 vs. 1.3 mg/L in PSNR06) in production. This optimized module was subsequently extended to construct downstream pathways for resveratrol and apigenin biosynthesis, enabling the production of multiple polyphenols from xylose. Furthermore, we identified and implemented a previously uncharacterized flavone synthase from Artemisia argyi ( Aa FNS), which enabled highly efficient conversion of naringenin to apigenin with a molar conversion rate of 81%, exceeding those of previously reported enzymes in S. cerevisiae . Collectively, this work establishes a modular yeast platform that couples xylose metabolism with plant secondary metabolite biosynthesis, demonstrating the feasibility of producing diverse polyphenols from lignocellulose-derived substrates. This integrated engineering strategy provides a foundation for sustainable and scalable biomanufacturing of high-value medicinal compounds.