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<p>Flavonoid diversity arises from modifications of a few precursors by tailored enzymes, yet the complexity of their evolved metabolic networks complicates pathway elucidation and design. Here, by combining chromosome-scale genome assembly with large-scale transcriptome analysis, we identify and reconstruct the glabridin biosynthetic pathway in yeast, enabling de novo production of this antioxidant flavonoid from <i>Glycyrrhiza glabra</i> L. By analyzing 183 licorice transcriptomes, we discover four classes of enzymes capable of modify isoflavan scaffolds. Among 13 theoretical routes, we validate six functional pathways, revealing a ladder-like, multi-route tailoring network. This network features a multi-step “protection–deprotection” mechanism driven by a dynamic methylation–demethylation cycle that regulate intermediate hydrophilicity and enzyme affinity, thereby enabling species-specific glabridin synthesis. Reconstruction of this network in yeast shows that metabolic redundancy and interconnectivity enhance robustness and yield compared to single-route designs. These results establish a biosynthetic paradigm with broad implications for natural product discovery and biomanufacturing.</p>

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Discover the maze-like network for glabridin biosynthesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月31日

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  • Zhen Zhang,
  • Wenqiang Li,
  • Fanze Meng,
  • Yanming Jin,
  • Wentao Sun,
  • Qina Kuang,
  • Shichao Ren,
  • Wei Liu,
  • Liang Zhang,
  • Lei Qin,
  • Bo Lv,
  • Haiyang Jia,
  • Chun Li

摘要

Flavonoid diversity arises from modifications of a few precursors by tailored enzymes, yet the complexity of their evolved metabolic networks complicates pathway elucidation and design. Here, by combining chromosome-scale genome assembly with large-scale transcriptome analysis, we identify and reconstruct the glabridin biosynthetic pathway in yeast, enabling de novo production of this antioxidant flavonoid from Glycyrrhiza glabra L. By analyzing 183 licorice transcriptomes, we discover four classes of enzymes capable of modify isoflavan scaffolds. Among 13 theoretical routes, we validate six functional pathways, revealing a ladder-like, multi-route tailoring network. This network features a multi-step “protection–deprotection” mechanism driven by a dynamic methylation–demethylation cycle that regulate intermediate hydrophilicity and enzyme affinity, thereby enabling species-specific glabridin synthesis. Reconstruction of this network in yeast shows that metabolic redundancy and interconnectivity enhance robustness and yield compared to single-route designs. These results establish a biosynthetic paradigm with broad implications for natural product discovery and biomanufacturing.