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

Abstract

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.

An Optimized Proteomics Approach Reveals Novel Alternative Proteins in Mouse Liver Development

“…The normalized collision energy was set as 30. PRM data (tier 3 level) were processed with Skyline (version 21.1) software as described previously ( 49 ). Predicted retention time and MS/MS spectra were calculated based on two deep learning tools, DeepRT ( 50 ) and pDeep2 ( 51 ), respectively.…”

Bioactive components and mechanisms of Pu-erh tea in improving levodopa metabolism in rats through COMT inhibition

“…14,15 Recent reports have highlighted a variety of natural compounds showing inhibition of COMT activity. For example, herbal purified components (e.g., rutin, quercetin, baicalein, myricetin, and celastrol) successively discovered and isolated from a variety of medicinal plants were found to have COMT inhibitory activity, 16,17 which inspired the search for novel COMT inhibitors. 18 These natural inhibitors have gained increasing popularity for their broad applicability, safety profile, and reduced side effects compared to their synthetic counterparts.…”

Degradation‐Based Protein Profiling: A Case Study of Celastrol

“…It exhibits a wide range of biological activities in tumor therapy, [ 8 ] immune inflammation, [ 9 ] neurodegenerative diseases, [ 10 ] and metabolic disorders. [ 11 ] Although some studies have revealed molecular targets and signaling pathways of celastrol, such as the PI3K/AKT pathway, [ 12 ] NF‐κB pathway, [ 13 ] STAT3, [ 14 ] HSP90, [ 15 ] and proteasome, [ 16 ] among others, [ 17 ] its exact mechanism of action remains incompletely understood. Moreover, challenges like poor water solubility, low bioavailability, narrow therapeutic window, and potential adverse reactions severely hinder its clinical application.…”