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Background <p>Emodin and its derivatives are important bioactive anthraquinones from rhubarb, with diverse pharmacological activities. Physcion, an <i>O</i>-methylated derivative of emodin, is a promising plant-derived fungicide and pharmaceutical lead. However, plant extraction yields are low and land-intensive, while microbial production is hampered by inefficient conversion and byproduct accumulation.</p> Results <p>Here, we identify a cytochrome P450 enzyme (CYP-H6231) that, with its dedicated redox partner cytochrome P450 reductase (CPR-H10273), converts emodin to ω-hydroxyemodin in <i>Aspergillus terreus</i>. Deletion of CYP-H6231 increased physcion titer by 1.8-fold and significantly improved product purity. Further engineering, via 3-<i>O</i>-methyltransferase overexpression, SAM pathway enhancement, and enzyme fusion, yielded only modest improvement (up to 37%), likely due to compromised strain robustness from the loss of CYP-H6231 mediated detoxification. Structural modeling and mutagenesis of CYP-H6231 revealed key residues for substrate recognition and catalysis.</p> Conclusions <p>This study reveals a detoxification bottleneck in anthraquinone biosynthesis and establishes two improved <i>A. terreus</i> platforms for scalable production of physcion and emodin, respectively, highlighting trade-offs between pathway efficiency and cellular fitness.</p>

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Multi-layered engineering of Aspergillus terreus enhances biosynthesis of the plant-derived fungicide physcion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月13日

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  • Zilin Ren,
  • Yingying Xue,
  • Ning Xu,
  • Dandan Feng,
  • Ce Geng,
  • Yongsong Wu,
  • Dan Liu,
  • Linshui Zhao,
  • Xiaoxi Zhang,
  • Honglei Ma,
  • Xuenian Huang,
  • Feifei Qi,
  • Xuefeng Lu

摘要

Background

Emodin and its derivatives are important bioactive anthraquinones from rhubarb, with diverse pharmacological activities. Physcion, an O-methylated derivative of emodin, is a promising plant-derived fungicide and pharmaceutical lead. However, plant extraction yields are low and land-intensive, while microbial production is hampered by inefficient conversion and byproduct accumulation.

Results

Here, we identify a cytochrome P450 enzyme (CYP-H6231) that, with its dedicated redox partner cytochrome P450 reductase (CPR-H10273), converts emodin to ω-hydroxyemodin in Aspergillus terreus. Deletion of CYP-H6231 increased physcion titer by 1.8-fold and significantly improved product purity. Further engineering, via 3-O-methyltransferase overexpression, SAM pathway enhancement, and enzyme fusion, yielded only modest improvement (up to 37%), likely due to compromised strain robustness from the loss of CYP-H6231 mediated detoxification. Structural modeling and mutagenesis of CYP-H6231 revealed key residues for substrate recognition and catalysis.

Conclusions

This study reveals a detoxification bottleneck in anthraquinone biosynthesis and establishes two improved A. terreus platforms for scalable production of physcion and emodin, respectively, highlighting trade-offs between pathway efficiency and cellular fitness.