De novo flavonoid production in engineered Escherichia coli

Abstract

Flavonoids are plant-derived natural compounds belonging to the large group of polyphenols. These molecules have a wide range of applications in the pharmaceutical, nutraceutical, and cosmetic industries due to their well-documented antioxidant, anti-inflammatory, and antimicrobial properties. However, their extraction from plant sources is limited by low yields, seasonal variability, and complex purification processes, making large-scale production challenging. Chemical synthesis is often not a viable alternative because of high production costs and the environmental impact associated with the use of toxic reagents and solvents. Consequently, microbial bioproduction through metabolic engineering has emerged as a sustainable and efficient alternative. In this context, Escherichia coli has become a leading microbial chassis for flavonoid production. The present review summarizes the advances in engineering E. coli for the de novo heterologous biosynthesis of flavonoids, including de novo production of flavanones, flavones, flavonols, prenylflavonoids, glycosylated flavonoids, and methylated flavonoids. Furthermore, the present review discusses the major metabolic and enzymatic bottlenecks that currently limit industrial-scale de novo flavonoid production. These challenges include insufficient precursor supply, suboptimal performance of plant-derived enzymes, cofactor imbalance, accumulation of toxic intermediates, and product toxicity. Strategies to overcome these limitations and enhance flavonoid titers, yields, and structural diversity are also highlighted. By integrating these approaches, E. coli emerges as a robust, sustainable, and economically competitive platform for large-scale flavonoid production.