Enhanced production of cis-13,16-docosadienoic acid in Yarrowia lipolytica via systematic metabolic engineering
Abstract
Abstract Cis-13,16-Docosadienoic acid (DDA) is an omega-6 polyunsaturated fatty acid with potential applications in the food and health sectors. Although DDA has been previously synthesized using Yarrowia lipolytica Po1f, several bottlenecks continue to limit further improvements in its production. In this study, systematic metabolic engineering was employed to enhance DDA biosynthesis in Y. lipolytica . First, the intracellular supply of linoleic acid (LA), the key precursor for DDA synthesis, was increased by screening and overexpressing heterologous Δ12-desaturases. Second, the two-step elongation pathway converting LA to DDA was optimized through comparison of two Δ9-elongases; however, fusion expression of the two elongation enzymes did not further improve DDA production. Third, co-overexpression of the two elongation genes, combined with evaluation of different promoters for driving Eh ELO1 expression, was implemented to enhance the second elongation step. Finally, disruption of PEX10 was tested as a potential strategy to block fatty acid degradation, but this approach did not improve DDA production. Through the combination of the effective strategies described above, the engineered strain YL-11 achieved a DDA content of 0.47% of total fatty acids (TFAs), corresponding to a titer of 5.34 mg/L in shake-flask cultures without fermentation optimization— the highest DDA titer reported to date at this scale. These results demonstrate the potential of microbial platforms as…
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