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<p>Azetidine is a prominent pharmacophore present in dozens of drug-related molecules of both natural and synthetic origins. But how nature builds this moiety has long remained enigmatic. Here we address the full deciphering of a two-metalloenzyme cascade leading to polyoximic acid, an azetidine-containing moiety of the fungicide polyoxin. We demonstrate that the PolE enzyme functions as an Fe<sup>2+</sup>/pterin-dependent <span>l</span>-isoleucine desaturase. Moreover we illustrate that PolF is a new member of the emerging haem-oxygenase-like diiron oxidases, converting the desaturated <span>l</span>-isoleucine to polyoximic acid via an intramolecular C–N cyclization. Remarkably, we also establish that PolF exhibits dual functionality, orchestrating the sequential desaturation and cyclization with <span>l</span>-isoleucine as the initial substrate. Finally, our combined structural and quantum-mechanics/molecular-mechanics studies show that the PolF enzyme employs an extraordinary mechanism for the construction of the azetidine-containing moiety. These findings expand our knowledge on the catalysis of metalloenzymes and open the way for rational access of more azetidine-related molecules.</p><p></p>

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A two-metalloenzyme cascade constructs the azetidine-containing pharmacophore

  • 期刊论文

  • 发表日期：

    2025年9月30日

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  • Rong Gong,
  • Yao Qu,
  • Jia Liu,
  • Xuan Zhang,
  • Liwei Zhou,
  • Zhu Tian,
  • Xinyue Zeng,
  • Boyu Jin,
  • Zhen Li,
  • Le Yu,
  • Ruyi Chen,
  • Yang Zhou,
  • Langxing Liao,
  • Liulin Yang,
  • Xuemin Song,
  • You-Sheng Cai,
  • Kun Shen,
  • Zixin Deng,
  • Zhengyu Zhang,
  • Binju Wang,
  • Wenqing Chen

摘要

Azetidine is a prominent pharmacophore present in dozens of drug-related molecules of both natural and synthetic origins. But how nature builds this moiety has long remained enigmatic. Here we address the full deciphering of a two-metalloenzyme cascade leading to polyoximic acid, an azetidine-containing moiety of the fungicide polyoxin. We demonstrate that the PolE enzyme functions as an Fe2+/pterin-dependent l-isoleucine desaturase. Moreover we illustrate that PolF is a new member of the emerging haem-oxygenase-like diiron oxidases, converting the desaturated l-isoleucine to polyoximic acid via an intramolecular C–N cyclization. Remarkably, we also establish that PolF exhibits dual functionality, orchestrating the sequential desaturation and cyclization with l-isoleucine as the initial substrate. Finally, our combined structural and quantum-mechanics/molecular-mechanics studies show that the PolF enzyme employs an extraordinary mechanism for the construction of the azetidine-containing moiety. These findings expand our knowledge on the catalysis of metalloenzymes and open the way for rational access of more azetidine-related molecules.