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<p>Prostaglandin F<sub>2α</sub> (PGF<sub>2α</sub>) is an important lipid mediator with diverse physiological activities, but its reliance on chemical synthesis presents challenges and limitations, driving the need for efficient microbial fermentation. This study engineered the oleaginous yeast <i>Yarrowia lipolytica</i> to establish a microbial platform for the de novo biosynthesis of PGF<sub>2α</sub> from glucose. Firstly, in vitro biotransformation of arachidonic acid (ARA) was achieved using engineered <i>Y. lipolytica</i> expressing prostaglandin H synthase and prostaglandin F synthase. Subsequently, the complete biosynthetic pathway was reconstituted in vivo. To overcome the rate-limiting Δ-8 desaturation step, a high-efficiency Δ-8 desaturase from <i>I. galbana</i> was selected, and a Δ9-elongase/Δ8-desaturase fusion protein with a GGGGS linker was constructed. Further systematic metabolic engineering including dual organelle engineering targeting the endoplasmic reticulum and lipid droplets, and enhanced acetyl-CoA supply via carnitine O-acetyltransferase (Cat2) overexpression - a strategy that proved more effective than regulating NADPH generation. Finally, fermentation optimization with the optimized YAO medium significantly boosted PGF<sub>2α</sub> production. These combined metabolic engineering strategies enabled <i>Y. lipolytica</i> de novo production of PGF<sub>2α</sub> from glucose, reaching a titer of 32.63 μg/L (nearly 3.58 μg/g DCW). Overall, this research offers a promising platform for advancing the green biosynthesis of PGF<sub>2α</sub> and other prostaglandins.</p>

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Improved de novo production of prostaglandin F2α from glucose with engineered Yarrowia lipolytica strains

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月20日

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  • Guo-Wei He,
  • La-Mei Ding,
  • Xiao Fan,
  • Chong Wang,
  • Xiang-Yang Lu,
  • Yun Tian,
  • Xiao-Jun Ji,
  • He Huang,
  • Hu-Hu Liu

摘要

Prostaglandin F2α (PGF2α) is an important lipid mediator with diverse physiological activities, but its reliance on chemical synthesis presents challenges and limitations, driving the need for efficient microbial fermentation. This study engineered the oleaginous yeast Yarrowia lipolytica to establish a microbial platform for the de novo biosynthesis of PGF2α from glucose. Firstly, in vitro biotransformation of arachidonic acid (ARA) was achieved using engineered Y. lipolytica expressing prostaglandin H synthase and prostaglandin F synthase. Subsequently, the complete biosynthetic pathway was reconstituted in vivo. To overcome the rate-limiting Δ-8 desaturation step, a high-efficiency Δ-8 desaturase from I. galbana was selected, and a Δ9-elongase/Δ8-desaturase fusion protein with a GGGGS linker was constructed. Further systematic metabolic engineering including dual organelle engineering targeting the endoplasmic reticulum and lipid droplets, and enhanced acetyl-CoA supply via carnitine O-acetyltransferase (Cat2) overexpression - a strategy that proved more effective than regulating NADPH generation. Finally, fermentation optimization with the optimized YAO medium significantly boosted PGF2α production. These combined metabolic engineering strategies enabled Y. lipolytica de novo production of PGF2α from glucose, reaching a titer of 32.63 μg/L (nearly 3.58 μg/g DCW). Overall, this research offers a promising platform for advancing the green biosynthesis of PGF2α and other prostaglandins.