De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories

Liu, Quanli,1988Chalmers tekniska högskola,Chalmers University of Technology,Novo Nordisk Fonden,Novo Nordisk Foundation (författare)

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.

Liu, Yi,1986Novo Nordisk Fonden,Novo Nordisk Foundation,Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)liuyi (författare)
Li, Gang,1991Chalmers tekniska högskola,Chalmers University of Technology,Novo Nordisk Fonden,Novo Nordisk Foundation(Swepub:cth)gangl (författare)
Savolainen, Otto,1982Chalmers tekniska högskola,Chalmers University of Technology,Itä-Suomen Yliopisto,University of Eastern Finland(Swepub:cth)sotto (författare)
Chen, Yun,1978Novo Nordisk Fonden,Novo Nordisk Foundation,Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)yunc (författare)
Nielsen, Jens B,1962Novo Nordisk Fonden,Novo Nordisk Foundation,Danmarks Tekniske Universitet,Technical University of Denmark,BioInnovation Institute (BII),Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)nielsenj (författare)
Chalmers tekniska högskolaNovo Nordisk Fonden (creator_code:org_t)

Ingår i:Nature Communications: Springer Science and Business Media LLC12:12041-17232041-1723

Av författaren/redakt...: Liu, Quanli, 198 ...; Liu, Yi, 1986; Li, Gang, 1991; Savolainen, Otto ...; Chen, Yun, 1978; Nielsen, Jens B, ...

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