Metabolic Engineering of Complex Flavonoid in Microbes

Flavonoid compounds are one of the largest natural products from plants. Many of the flavonoids have nutritional and pharmaceutical values. In plants, flavonoids are synthesized from the phenylpropanoid pathway. Plants can re-direct more than 20% of carbon fixed by photosynthesis into the phenylpropanoid pathway. However, efficient production of flavonoids in engineered microbes has been challenging. For complex flavonoid compounds with extensive modifications, such as hydroxylation, methoxylation, and prenylation of the core flavonoid rings, to achieve high titter and high yield is very difficult. We have applied various engineering “tricks” to improve flavonoid biosynthesis in microbial systems. Starting from an improved chassis, we built metabolic channels between key enzymes, developed transporters to facilitate the movement of final products, regenerated key co-factors through pathway manipulations, combined different pathways using enzymes from different organisms, and optimized the expression of several major classes of enzymes. These efforts allowed us to engineer the biosynthesis of several high-value flavonoid compounds with significant nutraceutical values.