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<p>Transfer RNA methyltransferases (tRNA MTases) catalyze site-specific methylation on tRNAs, a critical process that ensures the stability and functionality of tRNA molecules, thereby maintaining cellular homeostasis of tRNA methylation. Recent studies have illuminated the structural diversity, specific substrate recognition, and conserved catalytic mechanisms of tRNA MTases, revealing how their dysregulation contributes to various diseases, including cancers and neurodevelopmental disorders. This review integrates these advances, exploring the challenges of achieving precise substrate recognition and modification in the context of complex and specific tRNA modification landscape, while emphasizing the crucial role of tRNA MTases in disease pathogenesis. The identification of small-molecule inhibitors targeting specific tRNA MTases marks a promising step toward the development of novel therapies. With continued research into the broader biological functions and regulatory mechanisms of tRNA MTases, these insights hold great potential to drive clinical advancements and therapeutic innovations.</p>

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Targeting tRNA methyltransferases: from molecular mechanisms to drug discovery

  • 期刊论文

  • 发表日期：

    2025年5月7日

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  • Yanrong Gao,
  • Xinyu Liu,
  • Jiazhi Li

摘要

Transfer RNA methyltransferases (tRNA MTases) catalyze site-specific methylation on tRNAs, a critical process that ensures the stability and functionality of tRNA molecules, thereby maintaining cellular homeostasis of tRNA methylation. Recent studies have illuminated the structural diversity, specific substrate recognition, and conserved catalytic mechanisms of tRNA MTases, revealing how their dysregulation contributes to various diseases, including cancers and neurodevelopmental disorders. This review integrates these advances, exploring the challenges of achieving precise substrate recognition and modification in the context of complex and specific tRNA modification landscape, while emphasizing the crucial role of tRNA MTases in disease pathogenesis. The identification of small-molecule inhibitors targeting specific tRNA MTases marks a promising step toward the development of novel therapies. With continued research into the broader biological functions and regulatory mechanisms of tRNA MTases, these insights hold great potential to drive clinical advancements and therapeutic innovations.