Engineering yeast phospholipid metabolism for de novo oleoylethanolamide production

• Published in: Nature chemical biology Vol. 16; no. 2; pp. 197 - 205
• Main Authors: Liu, Yi, Liu, Quanli, Krivoruchko, Anastasia, Khoomrung, Sakda, Nielsen, Jens
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.02.2020
• Subjects: Acyl Coenzyme A - genetics; CDPdiacylglycerol-Serine O-Phosphatidyltransferase - genetics; CDPdiacylglycerol-Serine O-Phosphatidyltransferase - metabolism; Coenzyme A Ligases - genetics; Combinatorial analysis; Deregulation; Endocannabinoids - biosynthesis; Endocannabinoids - genetics; Engineering; Enzymes; Enzymes - genetics; Enzymes - metabolism; Escherichia coli Proteins - genetics; Escherichia coli Proteins - metabolism; Gene Expression Regulation, Fungal; Glucose - metabolism; Homeostasis; Lipid metabolism; Lipids; Lysophospholipase - genetics; Lysophospholipase - metabolism; Membrane structures; Membranes; Metabolic Engineering - methods; Metabolism; Microorganisms; Microorganisms, Genetically-Modified; Monoacylglycerol Lipases - genetics; Monoacylglycerol Lipases - metabolism; Oleic acid; Oleic Acids - biosynthesis; Oleic Acids - genetics; Optimization; Organelles; Organic chemistry; Periplasmic Proteins - genetics; Periplasmic Proteins - metabolism; Phospholipids; Phospholipids - genetics; Phospholipids - metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Yeast; Yeasts
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/s41589-019-0431-2

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 and a yield on glucose of 405.8 µg g . 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.