Systematic Metabolic Engineering of Yarrowia lipolytica for Efficient Production of Docosahexaenoic Acid

Docosahexaenoic acid (DHA), an important ω3 polyunsaturated fatty acid (PUFA), is widely applied in health products and infant formulas due to its significant physiological functions for human health. The traditional sources of deep-sea fish and shrimp extraction have limited industrialization and sustainable synthesis. Yarrowia lipolytica is an excellent host for PUFA synthesis. However, there are limited reports on DHA production in Y. lipolytica. In this study, Y. lipolytica was engineered to successfully produce DHA through systematic metabolic engineering, including the screening of high-efficiency elongase/desaturase, increasing the copy number of key genes, and promoting the storage of DHA by substituting acyltransferases with DHA-CoA preference. Finally, the DHA titer of the engineered strain reached up to 9.06 g/L, with a content of 36.8% in a 5 L bioreactor, representing the highest yield reported to date in yeast. This study broadened the methods for the green and sustainable synthesis of DHA.