Yi LiuQuanli LiuAnastasia KrivoruchkoSakda KhoomrungJens NielsenDanmarks Tekniske UniversitetFaculty of Medicine, Siriraj Hospital, Mahidol UniversityChalmers University of TechnologyBioInnovation Institute2020-01-272020-01-272019-01-01Nature Chemical Biology. (2019)15524469155244502-s2.0-85076479390https://repository.li.mahidol.ac.th/handle/20.500.14594/50386© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Phospholipids, the most abundant membrane lipid components, are crucial in maintaining membrane structures and homeostasis for biofunctions. As a structurally diverse and tightly regulated system involved in multiple organelles, phospholipid metabolism is complicated to manipulate. Thus, repurposing phospholipids for lipid-derived chemical production remains unexplored. Herein, we develop a Saccharomyces cerevisiae platform for de novo production of oleoylethanolamide, a phospholipid derivative with promising pharmacological applications in ameliorating lipid dysfunction and neurobehavioral symptoms. Through deregulation of phospholipid metabolism, screening of biosynthetic enzymes, engineering of subcellular trafficking and process optimization, we could produce oleoylethanolamide at a titer of 8,115.7 µg l−1 and a yield on glucose of 405.8 µg g−1. Our work provides a proof-of-concept study for systemically repurposing phospholipid metabolism for conversion towards value-added biological chemicals, and this multi-faceted framework may shed light on tailoring phospholipid metabolism in other microbial hosts.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1038/s41589-019-0431-2