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
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Novo Nordisk Foundation
Yi Liu
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Novo Nordisk Foundation
Gang Li
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Novo Nordisk Foundation
Otto Savolainen
University of Eastern Finland
Chalmers, Biology and Biological Engineering, Infrastructures
Yun Chen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Novo Nordisk Foundation
Jens B Nielsen
Novo Nordisk Foundation
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Technical University of Denmark (DTU)
BioInnovation Institute
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 12 1 6085Subject Categories (SSIF 2011)
Production Engineering, Human Work Science and Ergonomics
Other Mechanical Engineering
Biocatalysis and Enzyme Technology
DOI
10.1038/s41467-021-26361-1