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

doi:10.1007/s13659-025-00502-1

应用天然产物 ›› 2025, Vol. 15 ›› Issue (3): 21-21.DOI: 10.1007/s13659-025-00502-1

• ORIGINAL ARTICLES • 下一篇

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

Haoqi Dong^1,2, Xinni Yang¹, Peiying Wang^2,3, Weiya Huang^2,3, Liang Zhang¹, Song Song⁴, Jiangxin Liu¹

1. State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China;
2. University of Chinese Academy of Sciences, Beijing, 100049, China;
3. Yunnan University, Kunming, 650500, China;
4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China

收稿日期:2024-12-18 接受日期:2025-02-26 出版日期:2025-06-24 发布日期:2025-06-18
通讯作者: Jiangxin Liu Email:E-mail:liujiangxin@mail.kib.ac.cn
基金资助:
This work was supported by Yunnan Fundamental Research Projects (Grant No. 202201AT070183), Biological Medicine Special Project of Yunnan (202402AA310015), the Ten thousand-talents program of Yunnan Province to Jiangxin Liu, and the State Key Laboratory of Natural and Biomimetic Drugs, Peking University.

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

Haoqi Dong^1,2, Xinni Yang¹, Peiying Wang^2,3, Weiya Huang^2,3, Liang Zhang¹, Song Song⁴, Jiangxin Liu¹

1. State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China;
2. University of Chinese Academy of Sciences, Beijing, 100049, China;
3. Yunnan University, Kunming, 650500, China;
4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China

Received:2024-12-18 Accepted:2025-02-26 Online:2025-06-24 Published:2025-06-18
Supported by:
This work was supported by Yunnan Fundamental Research Projects (Grant No. 202201AT070183), Biological Medicine Special Project of Yunnan (202402AA310015), the Ten thousand-talents program of Yunnan Province to Jiangxin Liu, and the State Key Laboratory of Natural and Biomimetic Drugs, Peking University.

摘要/Abstract

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.

关键词: Natural product, Target identification, Chemical proteomics, Target verification

Abstract: 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.

Key words: Natural product, Target identification, Chemical proteomics, Target verification

Haoqi Dong, Xinni Yang, Peiying Wang, Weiya Huang, Liang Zhang, Song Song, Jiangxin Liu. Identification and verification of methylenetetrahydrofolate dehydrogenase 1-like protein as the binding target of natural product pseudolaric acid A[J]. 应用天然产物, 2025, 15(3): 21-21.

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

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

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