Research Article | Open Access

Volume 2025 |Article ID 100021 | https://doi.org/10.1016/j.bidere.2025.100021

De novo biosynthesis of cannabinoids and their analogs in Yarrowia lipolytica

Yuxiang Hong,^1,2 Yang Gu,³ Dewei Lin,¹ Zizhao Wu,¹ Wenhao Chen,¹ Tianjian Lu,¹ Pornpatsorn Lertphadungkit,¹ Jingbo Ma,⁴ Haili Wang,⁵ Bo Zhou,⁵ Gil Bar-Sela ,^2,6 Idan Cohen ,⁶ Peng Xu ^1,7

¹Department of Chemical Engineering, Guangdong Technion-Israel Institute of Technology, Shantou, Guangdong, 515063, China
²The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 320002, Israel
³School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, 210023, China
⁴College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, Anhui, 237012, China
⁵Chemistry and Chemical Engineering Guangdong Laboratory, Shantou, 5l5031, China
⁶Oncology and Hematology Division, Cancer Center, Emek Medical Center, Afula, 1834111, Israel
⁷Center for Lipid Engineering, Muyuan Laboratory, Zhengzhou, 450016, Henan, China

Abstract

Cannabis sativa has long been a cornerstone of both medicinal and cultural practices, with its therapeutic use spanning over 2700 years. Central to its therapeutic effects are cannabinoids, which interact with the endocannabinoid system to influence various physiological processes such as anxiety, pain, and inflammation. Despite its benefits, cannabinoid production faces challenges and scarcity from plant extraction. This work leverages Yarrowia lipolytica as a platform for cannabinoid biosynthesis. By optimizing the precursor supply, engineering biomolecular condensate-like dual prenyltransferase expression and expanding endogenous metabolism with a noncanonical polyketide synthase, we achieved the de novo biosynthesis of various cannabinoids and their analogs. Our engineered Y. lipolytica produced ∼3.5 mg/L cannabigerolic acid, 18.8 mg/L orsellinic acid, and 0.5 mg/L cannabigerorcinic acid. Additionally, the CBGA titer reached 15.7 mg/L with olivetolic acid supplementation. This work demonstrates the versatility of Y. lipolytica as a promising host for the production of cannabinoids and their analogs, which opens avenues for further research and medicinal applications.