De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories

Quanli Liu, Yi Liu, Gang Li, Otto Savolainen, Yun Chen and Jens Nielsen ()
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Quanli Liu: Chalmers University of Technology
Yi Liu: Chalmers University of Technology
Gang Li: Chalmers University of Technology
Otto Savolainen: Chalmers University of Technology
Yun Chen: Chalmers University of Technology
Jens Nielsen: Chalmers University of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26361-1

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