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<p>Brassinolide (BL) is the most bioactive plant growth regulator among Brassinosteroids (BRs), belonging to the sixth class of plant hormones. However, its low natural abundance limits large-scale agricultural applications. An unnatural sterol, 24-epi-ergosterol, was proposed as a semi-synthetic precursor for economic production of BL. Here, we constructed a synthetic pathway for 24-epi-ergosterol in <i>Yarrowia lipolytica</i>, which has abundant acetyl-CoA content and a hydrophobic intracellular environment. Initially, we introduced a mutant plant-derived Δ<sup>24(28)</sup> sterol reductase (Dwf1) into <i>Y. lipolytica</i> to enable 24-epi-ergosterol production. The production of 24-epi-ergosterol was subsequently enhanced by regulating sterol homeostasis, optimizing transcriptional regulators, and overexpressing key pathway genes. Next, the accumulation of 24-epi-ergosterol was further improved by increasing acetyl-CoA levels and adjusting lipid metabolism. Finally, the 24-epi-ergosterol production reached 1626.85&#xa0;mg/L after optimizing the fermentation conditions and performing a fed-batch culture in a 2 L fermenter. This study represents the first successful de novo synthesis of 24-epi-ergosterol in <i>Y. lipolytica</i>, offering a novel approach for the industrial production of BL.</p>

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Novel cell factory for the production of 24-epi-ergosterol, an un-natural semi-synthetic precursor for the production of brassinolide in Yarrowia lipolytica

  • 期刊论文

  • 发表日期：

    2025年3月10日

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  • Yuanying Wang,
  • Shuxian Liu,
  • Zeyu Sheng,
  • Yun Feng,
  • Yinmiao Wang,
  • Yiqi Jiang,
  • Li Zhu,
  • Mianbin Wu,
  • Lirong Yang,
  • Jianping Lin

摘要

Brassinolide (BL) is the most bioactive plant growth regulator among Brassinosteroids (BRs), belonging to the sixth class of plant hormones. However, its low natural abundance limits large-scale agricultural applications. An unnatural sterol, 24-epi-ergosterol, was proposed as a semi-synthetic precursor for economic production of BL. Here, we constructed a synthetic pathway for 24-epi-ergosterol in Yarrowia lipolytica, which has abundant acetyl-CoA content and a hydrophobic intracellular environment. Initially, we introduced a mutant plant-derived Δ24(28) sterol reductase (Dwf1) into Y. lipolytica to enable 24-epi-ergosterol production. The production of 24-epi-ergosterol was subsequently enhanced by regulating sterol homeostasis, optimizing transcriptional regulators, and overexpressing key pathway genes. Next, the accumulation of 24-epi-ergosterol was further improved by increasing acetyl-CoA levels and adjusting lipid metabolism. Finally, the 24-epi-ergosterol production reached 1626.85 mg/L after optimizing the fermentation conditions and performing a fed-batch culture in a 2 L fermenter. This study represents the first successful de novo synthesis of 24-epi-ergosterol in Y. lipolytica, offering a novel approach for the industrial production of BL.