Manipulation of sterol homeostasis for the production of 24-epi-ergosterol in industrial yeast

Yiqi Jiang, Zhijiao Sun, Kexin Lu, Zeyu Wu, Hailong Xue, Li Zhu, Guosi Li, Yun Feng, Mianbin Wu, Jianping Lin (), Jiazhang Lian () and Lirong Yang
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Yiqi Jiang: Zhejiang University
Zhijiao Sun: Zhejiang University
Kexin Lu: Zhejiang University
Zeyu Wu: Zhejiang University
Hailong Xue: Zhejiang University
Li Zhu: Zhejiang University
Guosi Li: Zhejiang University
Yun Feng: Zhejiang University
Mianbin Wu: Zhejiang University
Jianping Lin: Zhejiang University
Jiazhang Lian: Zhejiang University
Lirong Yang: Zhejiang University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Brassinolide (BL) is the most biologically active compound among natural brassinosteroids. However, the agricultural applications are limited by the extremely low natural abundance and the scarcity of synthetic precursors. Here, we employ synthetic biology to construct a yeast cell factory for scalable production of 24-epi-ergosterol, an un-natural sterol, proposed as a precursor for BL semi-synthesis. First, we construct an artificial pathway by introducing a Δ24(28) sterol reductase from plants (DWF1), followed by enzyme directed evolution, to enable de novo biosynthesis of 24-epi-ergosterol in yeast. Subsequently, we manipulate the sterol homeostasis (overexpression of ARE2, YEH1, and YEH2 with intact ARE1), maintaining a balance between sterol acylation and sterol ester hydrolysis, for the production of 24-epi-ergosterol, whose titer reaches to 2.76 g L−1 using fed-batch fermentation. The sterol homeostasis engineering strategy can be applicable for bulk production of other economically important phytosterols.

Date: 2023
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DOI: 10.1038/s41467-023-36007-z

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