Engineering yeast for the production of breviscapine by genomic analysis and synthetic biology approaches

The flavonoid extract from Erigeron breviscapus, breviscapine, has increasingly been used to treat cardio-and cerebrovascular diseases in China for more than 30 years, and plant supply of E. breviscapus is becoming insufficient to satisfy the growing market demand. Here we report an alternative strategy for the supply of breviscapine by building a yeast cell factory using synthetic biology. We identify two key enzymes in the biosynthetic pathway (flavonoid-7-O-glucuronosyltransferase and flavone-6-hydroxylase) from E. breviscapus genome and engineer yeast to produce breviscapine from glucose. After metabolic engineering and optimization of fed-batch fermentation, scutellarin and apigenin-7-O-glucuronide, two major active ingredients of breviscapine, reach to 108 and 185 mg l^-1, respectively. Our study not only introduces an alternative source of these valuable compounds, but also provides an example of integrating genomics and synthetic biology knowledge for metabolic engineering of natural compounds.