De novo biosynthesis of anticarcinogenic icariin in engineered yeast

Ting An; Guangyuan Lin; Yang Liu; Lei Qin; Yuquan Xu; Xudong Feng; Chun Li

doi:10.1016/j.ymben.2023.10.003

De novo biosynthesis of anticarcinogenic icariin in engineered yeast

Metab Eng. 2023 Nov:80:207-215. doi: 10.1016/j.ymben.2023.10.003. Epub 2023 Oct 16.

Authors

Ting An¹, Guangyuan Lin², Yang Liu³, Lei Qin², Yuquan Xu³, Xudong Feng⁴, Chun Li⁵

Affiliations

¹ Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, Department of Chemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, China.
² Key Lab for Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China.
³ Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
⁴ Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, Department of Chemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, China. Electronic address: xd.feng@bit.edu.cn.
⁵ Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, Department of Chemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, China; Key Lab for Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China; Center for Synthetic & Systems Biology, Tsinghua University, Beijing, 100084, China. Electronic address: lichun@tsinghua.edu.cn.

PMID: 37852432
DOI: 10.1016/j.ymben.2023.10.003

Abstract

Icariin (ICA) has wide applications in nutraceuticals and medicine with strong anticancer activities. However, the structural complexity and low abundance in plants of ICA lead to the unsustainable and high-cost supply from chemical synthesis and plant extraction. Here, the whole biosynthesis pathway of ICA was elucidated, then was constructed in Saccharomyces cerevisiae, including a 13-step heterologous ICA pathway from eleven kinds of plants as well as deletions or overexpression of ten yeast endogenous genes. Spatial regulation of 8-C-prenyltransferase to mitochondria and three-stage sequential control of 4'-O-methyltransferase, 3-OH rhamnosyltransferase, and 7-OH glycosyltransferase expression successfully achieved the de novo synthesis of ICA with a titer of 130 μg/L under shake-flask culture. The ICA synthesis from glucose represents the longest reconstructed pathway of flavonoid in microbe so far. This study provides a potential choice for the sustainable microbial production of number of complex flavonoids.

Keywords: Glycosylation; Icariin; Methylation; Prenylation; Saccharomyces cerevisiae; Temporospatial regulation.

MeSH terms

Flavonoids / genetics
Glucose / metabolism
Metabolic Engineering*
Saccharomyces cerevisiae* / genetics
Saccharomyces cerevisiae* / metabolism

Substances

icariin
Flavonoids
Glucose