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

• Published in: ACS chemical biology Vol. 17; no. 8; pp. 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: Journal Article
• Language: English
• Published: United States American Chemical Society 19.08.2022
• Subjects: Catechol O-Methyltransferase - chemistry; Catechol O-Methyltransferase Inhibitors - chemistry; Catechol O-Methyltransferase Inhibitors - metabolism; Catechol O-Methyltransferase Inhibitors - pharmacology; Mass Spectrometry; Pentacyclic Triterpenes
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.2c00011

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.