De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories.

Liu Q, Liu Y, Li G, Savolainen O, Chen Y, Nielsen J

Nat Commun 12 (1) 6085 [2021-10-19; online 2021-10-19]

Isoflavonoids comprise a class of plant natural products with great nutraceutical, pharmaceutical and agricultural significance. Their low abundance in nature and structural complexity however hampers access to these phytochemicals through traditional crop-based manufacturing or chemical synthesis. Microbial bioproduction therefore represents an attractive alternative. Here, we engineer the metabolism of Saccharomyces cerevisiae to become a platform for efficient production of daidzein, a core chemical scaffold for isoflavonoid biosynthesis, and demonstrate its application towards producing bioactive glucosides from glucose, following the screening-reconstruction-application engineering framework. First, we rebuild daidzein biosynthesis in yeast and its production is then improved by 94-fold through screening biosynthetic enzymes, identifying rate-limiting steps, implementing dynamic control, engineering substrate trafficking and fine-tuning competing metabolic processes. The optimized strain produces up to 85.4 mg L-1 of daidzein and introducing plant glycosyltransferases in this strain results in production of bioactive puerarin (72.8 mg L-1) and daidzin (73.2 mg L-1). Our work provides a promising step towards developing synthetic yeast cell factories for de novo biosynthesis of value-added isoflavonoids and the multi-phased framework may be extended to engineer pathways of complex natural products in other microbial hosts.

Chalmers Mass Spectrometry Infrastructure [Service]

PubMed 34667183

DOI 10.1038/s41467-021-26361-1

Crossref 10.1038/s41467-021-26361-1

pii: 10.1038/s41467-021-26361-1
pmc: PMC8526750

Publications 9.5.0