期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 6, 页码 1262-1267出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1715282115
关键词
phospholipids; free fatty acids; Saccharomyces cerevisiae; metabolic engineering; CRISPR
资金
- National Microscopy Infrastructure [VRRFI 2016-00968]
- Novo Nordisk Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Foundation for Strategic Research
- Novo Nordisk Fonden [NNF10CC1016517] Funding Source: researchfish
- NNF Center for Biosustainability [Yeast Cell Factories] Funding Source: researchfish
Bio-based production of fatty acids and fatty acid-derived products can enable sustainable substitution of petroleum-derived fuels and chemicals. However, developing new microbial cell factories for producing high levels of fatty acids requires extensive engineering of lipid metabolism, a complex and tightly regulated metabolic network. Here we generated a Saccharomyces cerevisiae platform strain with a simplified lipid metabolism network with high-level production of free fatty acids (FFAs) due to redirected fatty acid metabolism and reduced feedback regulation. Deletion of the main fatty acid activation genes (the first step in ss-oxidation), main storage lipid formation genes, and phosphatidate phosphatase genes resulted in a constrained lipid metabolic network in which fatty acid flux was directed to a large extent toward phospholipids. This resulted in simultaneous increases of phospholipids by up to 2.8-fold and of FFAs by up to 40-fold compared with wild-type levels. Further deletion of phospholipase genes PLB1 and PLB2 resulted in a 46% decrease in FFA levels and 105% increase in phospholipid levels, suggesting that phospholipid hydrolysis plays an important role in FFA production when phospholipid levels are increased. The multiple deletion mutant generated allowed for a study of fatty acid dynamics in lipid metabolism and represents a platform strain with interesting properties that provide insight into the future development of lipid-related cell factories.
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