Gallic Acid as a Non-Selective Inhibitor of α/β-Hydrolase Fold Enzymes Involved in the Inflammatory Process: The Two Sides of the Same Coin.

Marcos Hikari Toyama,Caroline Ramos Da Cruz Costa,Airam Rogero,Agatha Manzi De Carli,Laila Lucyane Ferreira De Moraes,Gustavo Antônio Fernandes,Mariana Novo Belchor,Marcos Antônio De Oliveira

doi:10.3390/pharmaceutics14020368

Marcos Hikari Toyama, Caroline Ramos Da Cruz Costa + Show 6 more

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https://doi.org/10.3390/pharmaceutics14020368

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Abstract

(1) Background: Gallic acid (GA) has been characterized as an effective anti-inflammatory, antivenom, and promising drug for therapeutic use. (2/3) Methods and Results: GA was identified from ethanolic extract of fresh pitanga (Eugenia uniflora) leaves, which was identified using commercial GA. Commercial GA neutralized the enzymatic activity of secretory PLA2 (sPLA2) by inhibiting the active site and inducing changes in the secondary structure of the enzyme. Pharmacological edema assays showed that GA strongly decreased edema when the compound was previously incubated with sPLA2. However, prior treatment of GA (30 min before) significantly increased the edema and myotoxicity induced by sPLA2. The molecular docking results of GA with platelet-acetylhydrolase (PAF-AH) and acetylcholinesterase reveal that this compound was able to interact with the active site of both molecules, inhibiting the hydrolysis of platelet-activating factor (PAF) and acetylcholine (ACh). (4) Conclusion: GA has a great potential application; however, our results show that this compound can also induce adverse effects in previously treated animals. Additionally, the increased edema and myotoxicity observed experimentally in GA-treated animals may be due to the inhibition of PAF-AH and Acetylcholinesterase.

Highlights

Gallic acid (GA) is widely present in the plant kingdom and can be found in its free form in vegetal tissues, in the esters form, or as conjugated esterified molecules
The big question in this study was: when animals are previously treated with GA, could this compound neutralize the inflammatory and myotoxic action induced by secretory PLA2 (sPLA2) from rattlesnake venom? in this short communication, we show that GA, when previously applied, increased the pharmacological effects induced by PLA2, and we reveal essential interactions of this compound with these crucial enzymes through molecular docking studies, an essential tool to understand in vitro and in vivo studies
Gallic acid can be a valuable compound in terms of raw material and it has the ability to act as an anti-inflammatory molecule inhibiting the sPLA2, as an antioxidant agent, and as a COX2 inhibitor [1,13,34,35]

Summary

Introduction

Gallic acid (GA) is widely present in the plant kingdom and can be found in its free form in vegetal tissues, in the esters form, or as conjugated esterified molecules. Α/βhydrolase fold proteins are a major superfamily of enzymes that catalyze a wide range of reactions, featuring a conserved Ser-His-Acid catalytic triad This family encompasses a variety of enzymes, including esterases, proteases, lipases, dehalogenases, peroxidases, and epoxide hydrolases. They all contain a catalytic triad composed of a nucleophile (typically serine, occasionally aspartate or cysteine), an anionic side chain, and an intervening histidine from the catalytic triad, located between the core and cap domains. This enzymatic fold is found throughout all domains of organisms, ranging from humans to plants, bacteria, and even viruses [6,7]. This characteristic has been found in several important enzymes involved in inflammation, such as intracellular and extracellular Platelet-Activating

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