Innovative approaches to polyphenol synthesis: combinatorial biosynthesis unveiled (flash presentation)

Abstract

Polyphenols, naturally present in plants, are recognized for their biological properties, including antioxidant, anti-inflammatory, anticancer, and estrogenic effects. Their remarkable potential positions polyphenols as promising candidates for therapeutic applications, driving a rapidly expanding market projected to reach $3.5 billion by 2032. However, polyphenols accumulate in low amounts over extended growth periods requiring substantial investments in water, land, and time. Therefore, the extraction and purification processes are inefficient, environmentally unfriendly, and expensive. Moreover, the supply chain is vulnerable to insecurities arising from pests and extreme weather conditions. Given these challenges, there has been a focused endeavor over the past decade to harness synthetic biology potential for polyphenol production. Our group has been dedicated to advancing the heterologous production of curcuminoids, flavonoids, prenylflavonoids, coumarins and furanocoumarins, in both model hosts, Escherichia coli and Saccharomyces cerevisiae. We have successfully enhanced these compounds production using genome engineering (CRISPR-Cas9), step-by-step optimization and combinatorial biosynthesis. Naringenin biosynthesis in E. coli achieved record-breaking titers from glucose (765.9 mg/L). Additionally, curcumin and prenylflavonoids were produced for the first time in S. cerevisiae and E. coli, respectively, also using glucose as substrate. These results mark a significant step forward in progressing the sustainable large-scale production of these valuable polyphenols.