Integrated Mass Spectrometry Reveals Celastrol As a Novel Catechol-O-methyltransferase Inhibitor

Natural product celastrol is known to have various biological activities, yet its molecular targets that correspond to many activities remain unclear. Here, we used multiple mass-spectrometry-based approaches to identify catechol-O-methyltransferase (COMT) as a major binding target of celastrol and...

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Bibliographic Details
Published in:ACS chemical biology 2022-08, Vol.17 (8), p.2003-2009
Main Authors: Guo, Haijun, Yang, Yang, Zhang, Qi, Deng, Jie-Ren, Yang, Ying, Li, Shuqi, So, Pui-Kin, Lam, Thomas C., Wong, Man-kin, Zhao, Qian
Format: Article
Language:English
Subjects:
Catechol O-Methyltransferase - chemistry
Catechol O-Methyltransferase Inhibitors - chemistry
Catechol O-Methyltransferase Inhibitors - metabolism
Catechol O-Methyltransferase Inhibitors - pharmacology
Mass Spectrometry
Pentacyclic Triterpenes
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Summary:Natural product celastrol is known to have various biological activities, yet its molecular targets that correspond to many activities remain unclear. Here, we used multiple mass-spectrometry-based approaches to identify catechol-O-methyltransferase (COMT) as a major binding target of celastrol and characterized their interaction comprehensively. Celastrol was found to inhibit the enzymatic activity of COMT and increased the dopamine level in neuroendocrine chromaffin cells significantly. Our study not only revealed a novel binding target of celastrol but also provided a new scaffold and cysteine hot spot for developing new generation COMT inhibitors in combating neurological disorders.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.2c00011