P. Srinivasan, C. Smolke
Aug 12, 2019
Citations
1
Influential Citations
58
Citations
Journal
Nature Communications
Abstract
Tropane alkaloids (TAs) are a class of phytochemicals produced by plants of the nightshade family used for treating diverse neurological disorders. Here, we demonstrate de novo production of tropine, a key intermediate in the biosynthetic pathway of medicinal TAs such as scopolamine, from simple carbon and nitrogen sources in yeast (Saccharomyces cerevisiae). Our engineered strain incorporates 15 additional genes, including 11 derived from diverse plants and bacteria, and 7 disruptions to yeast regulatory or biosynthetic proteins to produce tropine at titers of 6 mg/L. We also demonstrate the utility of our engineered yeast platform for the discovery of TA derivatives by combining biosynthetic modules from distant plant lineages to achieve de novo production of cinnamoyltropine, a non-canonical TA. Our engineered strain constitutes a starting point for future optimization efforts towards realizing industrial fermentation of medicinal TAs and a platform for the synthesis of TA derivatives with enhanced bioactivities. Tropane alkaloids (TAs) are a group of phytochemicals that are used to treat neurological disorders. Here, the authors engineer baker’s yeast to produce tropine, a key intermediate in the biosynthetic pathway of TAs, and cinnamoyltropine, a non-canonical TA, from simple carbon and nitrogen sources.