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<p>Natural product pseudolaric acid A (PAA), the main bioactive component from Traditional Chinese Medicine <i>Pseudolarix cortex</i> (“tujingpi”), is a promising anticancer agent. However, its potential molecular targets are not clear and this hinders its development. In this study, chemical proteomics approaches including activity-based protein profiling (ABPP) and drug affinity responsive target stability (DARTS) technology, followed by quantitative proteomics, were combined to reveal the target of PAA. Target validation was performed by NMR techniques and surface plasmon resonance. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) was identified and further confirmed to be the target of PAA. The direct interaction and binding mode between MTHFD1L and PAA were elaborated. PAA induced the accumulation of the reactive oxygen species (ROS) which mediates the antitumor effect. Transcriptome and network pharmacology analysis reveals the effects of PAA on the gene expressions of the associated pathways. Taken together, our findings proposed a new target that could be used for structure-based rational design and modifications of PAA.</p> Graphical abstract <p></p>

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Identification and verification of methylenetetrahydrofolate dehydrogenase 1-like protein as the binding target of natural product pseudolaric acid A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月2日

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  • Haoqi Dong,
  • Xinni Yang,
  • Peiying Wang,
  • Weiya Huang,
  • Liang Zhang,
  • Song Song,
  • Jiangxin Liu

摘要

Natural product pseudolaric acid A (PAA), the main bioactive component from Traditional Chinese Medicine Pseudolarix cortex (“tujingpi”), is a promising anticancer agent. However, its potential molecular targets are not clear and this hinders its development. In this study, chemical proteomics approaches including activity-based protein profiling (ABPP) and drug affinity responsive target stability (DARTS) technology, followed by quantitative proteomics, were combined to reveal the target of PAA. Target validation was performed by NMR techniques and surface plasmon resonance. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) was identified and further confirmed to be the target of PAA. The direct interaction and binding mode between MTHFD1L and PAA were elaborated. PAA induced the accumulation of the reactive oxygen species (ROS) which mediates the antitumor effect. Transcriptome and network pharmacology analysis reveals the effects of PAA on the gene expressions of the associated pathways. Taken together, our findings proposed a new target that could be used for structure-based rational design and modifications of PAA.

Graphical abstract