The inhibitory effect and mechanism of small molecules on acetic anhydride-induced BSA acetylation and aggregation
Xingli Huo1, Huijun Liu1, Shengjie Wang1
1Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Abstract:
Protein acetylation is a significant post-translational modification, and hyperacetylation results in amyloid aggregation, which is closely related to neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and so on). Therefore, it is significant to inhibit the hyperacetylation of proteins and their induced aggregation. In the present study, we aimed to explore the anti-acetylation and anti-amyloid properties of five small molecules (gallic acid, menadione, resveratrol, apigenin, and quercetin) in the process of acetic anhydride-induced protein hyperacetylation and its aggregation. Optical detection methods, such as SDS-PAGE, inverted fluorescence microscopy, and endogenous fluorescence spectroscopy, were used to investigate the effects of small molecules on protein acetylation, aggregation, and structure. In addition, fluorescence quenching and molecular docking techniques were used to explore the relationship between small molecules and acetylation. The results showed that gallic acid (200 μM), menadione (100 μM), quercetin (40 μM), resveratrol (5 μM), and apigenin (20 μM) (unmodified rates were 61.12 %, 67.76 %, 65.11 %, 62.66 %, and 67.81 %, respectively) had strong inhibitory effects on acetylation, and there was no significant difference (P < 0.05). In addition, gallic acid (200 μM), menadione (100 μM), and resveratrol (5 μM) (inhibition rates of 29.89 %, 26.53 %, and 26.09 %, respectively) had more substantial inhibitory effects on protein aggregation, indicating that the five small molecules could inhibit acetic anhydride-induced hyperacetylation and protein aggregation. The underlying mechanism might be that it could inhibit hyperacetylation and resist amyloid aggregation by interacting with proteins to occupy acetylation sites. Collectively, our findings showed that gallic acid, menadione, and resveratrol could potentially prevent and treat neurodegenerative diseases, such as Alzheimer's disease, by inhibiting acetylation and acetylation-induced aggregation.
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