Research Article | Open Access

Volume 2022 |Article ID 0002 | https://doi.org/10.34133/bdr.0002

De Novo Biosynthesis of Vindoline and Catharanthine in Saccharomyces cerevisiae

Di Gao,¹ Tengfei Liu,¹ Jucan Gao,^1,2 Junhao Xu,^1,2 Yuanwei Gou,^1,2 Yingjia Pan,^1,2 Dongfang Li,² Cuifang Ye,¹ Ronghui Pan,² Lei Huang,^1,2 Zhinan Xu,¹ Jiazhang Lian ^1,2,3

¹Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China.
²ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China
³Zhejiang Key Laboratory of Smart Biomaterials, Zhejiang University, Hangzhou 310027, China

Abstract

Vinblastine has been used clinically as one of the most potent therapeutics for the treatment of several types of cancer. However, the traditional plant extraction method suffers from unreliable supply, low abundance, and extremely high cost. Here, we use synthetic biology approach to engineer Saccharomyces cerevisiae for de novo biosynthesis of vindoline and catharanthine, which can be coupled chemically or biologically to vinblastine. On the basis of a platform strain with sufficient supply of precursors and cofactors for biosynthesis, we reconstituted, debottlenecked, and optimized the biosynthetic pathways for the production of vindoline and catharanthine. The vindoline biosynthetic pathway represents one of the most complicated pathways ever reconstituted in microbial cell factories. Using shake flask fermentation, our engineered yeast strains were able to produce catharanthine and vindoline at a titer of 527.1 and 305.1 μg·liter−1, respectively, without accumulating detectable amount of pathway intermediates. This study establishes a representative example for the production of valuable plant natural products in yeast.