Biosynthesis of plant vitexin-derived flavonoid glycosides in yeast
摘要
Post-modified flavonoids from plants exhibit diverse chemical structures and bioactivities, making them valuable in pharmaceuticals and health-promoting foods. Synthetic biology has facilitated the microbial synthesis of post-modified flavonoids as an alternative to traditional plant extraction. Nevertheless, de novo biosynthesis achieves only limited production levels (milligrams per litre). In this study, we aimed to develop yeast for the bioproduction of plant-derived medicinal flavonoid monoglycosides (vitexin and orientin) and diglycosides (2″-O-galactosylvitexin and 2″-O-galactosylorientin) in high yields. We elucidated the complete biosynthetic pathways in Komagataella phaffii, an industrial yeast. Systematic metabolic engineering of the building blocks (tyrosine, malonyl-coenzyme A and sugar donors) along with parallel pathways enhanced product titres to around 10 g l−1. Comparative omics analysis of the variations in flavonoid glycosides production on ethanol versus glucose revealed new targets to improve the synthesis. The integration of strategies for the generation of ATP, cofactor balancing and hydrolase inactivation boosted product titres to >26 g l−1. The described strains and procedures represent an important advance in the production of flavonoid glycosides from simple carbon sources.