De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories
Journal article, 2021

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.

Author

Quanli Liu

Novo Nordisk Foundation Center for Biosustainability

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Yi Liu

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Novo Nordisk Foundation Center for Biosustainability

Gang Li

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Novo Nordisk Foundation Center for Biosustainability

Otto Savolainen

University of Eastern Finland

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology, CMSI

Yun Chen

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Novo Nordisk Foundation Center for Biosustainability

Jens B Nielsen

BioInnovation Institute

Technical University of Denmark (DTU)

Novo Nordisk Foundation Center for Biosustainability

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Nature Communications

2041-1723 (ISSN)

Vol. 12 1 6085

Subject Categories

Production Engineering, Human Work Science and Ergonomics

Other Mechanical Engineering

Biocatalysis and Enzyme Technology

DOI

10.1038/s41467-021-26361-1

More information

Latest update

11/8/2021