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<p>Dehydroepiandrosterone (DHEA), a pivotal steroid hormone precursor, holds significant clinical and industrial value for its role in hormone synthesis. Traditional chemical and chemo-enzymatic production methods face challenges such as complex processes, low yields, and environmental concerns. This study presents a green, all-enzymatic route for the synthesis of DHEA from 4-androstene-3,17-dione (4-AD) using engineered molecular machines. By leveraging SpyCatcher-SpyTag and cohesin-dockerin interactions, we constructed dual- and triple-enzyme complexes to spatially organize 3β-ketosteroid isomerase, carbonyl reductase, and formate dehydrogenase. The dual-enzyme system achieved an 84% conversion rate for 10 g/L 4-AD, while the triple-enzyme complex further enhanced conversion to 90% (10 g/L) and 98% (2.5 g/L). This strategy overcomes the instability of the intermediate 5-androstene-3,17-dione (5-AD) through enzyme proximity, and eliminate chemical reactions. This work establishes a sustainable, highly efficient biocatalytic synthesis of DHEA, offering a novel strategy for challenging steroidal transformations and advancing green pharmaceutical manufacturing.</p>

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Highly efficient conversion of androstenedione into dehydroepiandrosterone through the construction of molecular machines

  • 期刊论文

  • 发表日期：

    2025年7月1日

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  • Minjie Li,
  • Xiaojun Wang,
  • Yue Fan,
  • Xuemei Li,
  • Yunfeng Cui,
  • Liangyan Zhu,
  • Xiangtao Liu,
  • Xi Chen,
  • Na Liu,
  • Yanbing Shen,
  • Jinhui Feng,
  • Jinku Bao,
  • Qiaqing Wu,
  • Dunming Zhu

摘要

Dehydroepiandrosterone (DHEA), a pivotal steroid hormone precursor, holds significant clinical and industrial value for its role in hormone synthesis. Traditional chemical and chemo-enzymatic production methods face challenges such as complex processes, low yields, and environmental concerns. This study presents a green, all-enzymatic route for the synthesis of DHEA from 4-androstene-3,17-dione (4-AD) using engineered molecular machines. By leveraging SpyCatcher-SpyTag and cohesin-dockerin interactions, we constructed dual- and triple-enzyme complexes to spatially organize 3β-ketosteroid isomerase, carbonyl reductase, and formate dehydrogenase. The dual-enzyme system achieved an 84% conversion rate for 10 g/L 4-AD, while the triple-enzyme complex further enhanced conversion to 90% (10 g/L) and 98% (2.5 g/L). This strategy overcomes the instability of the intermediate 5-androstene-3,17-dione (5-AD) through enzyme proximity, and eliminate chemical reactions. This work establishes a sustainable, highly efficient biocatalytic synthesis of DHEA, offering a novel strategy for challenging steroidal transformations and advancing green pharmaceutical manufacturing.