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Different roles for the acyl chain and the amine leaving group in the substrate selectivity of N-Acylethanolamine acid amidase
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2021-07-13 , DOI: 10.1080/14756366.2021.1912035
Andrea Ghidini 1 , Laura Scalvini 1 , Francesca Palese 2 , Alessio Lodola 1 , Marco Mor 1 , Daniele Piomelli 2, 3, 4
Affiliation  

Abstract

N-acylethanolamine acid amidase (NAAA) is an N-terminal nucleophile (Ntn) hydrolase that catalyses the intracellular deactivation of the endogenous analgesic and anti-inflammatory agent palmitoylethanolamide (PEA). NAAA inhibitors counteract this process and exert marked therapeutic effects in animal models of pain, inflammation and neurodegeneration. While it is known that NAAA preferentially hydrolyses saturated fatty acid ethanolamides (FAEs), a detailed profile of the relationship between catalytic efficiency and fatty acid-chain length is still lacking. In this report, we combined enzymatic and molecular modelling approaches to determine the effects of acyl chain and polar head modifications on substrate recognition and hydrolysis by NAAA. The results show that, in both saturated and monounsaturated FAEs, the catalytic efficiency is strictly dependent upon fatty acyl chain length, whereas there is a wider tolerance for modifications of the polar heads. This relationship reflects the relative stability of enzyme-substrate complexes in molecular dynamics simulations.



中文翻译:

酰基链和胺离去基团在 N-酰基乙醇胺酸酰胺酶底物选择性中的不同作用

摘要

N-酰基乙醇胺酸酰胺酶 (NAAA) 是一种N-末端亲核试剂 (Ntn) 水解酶催化内源性镇痛和抗炎剂棕榈酰乙醇酰胺 (PEA) 的细胞内失活。NAAA 抑制剂可以抵消这一过程,并在疼痛、炎症和神经退行性疾病的动物模型中发挥显着的治疗作用。虽然已知 NAAA 优先水解饱和脂肪酸乙醇酰胺 (FAE),但仍缺乏催化效率与脂肪酸链长度之间关系的详细概况。在本报告中,我们结合酶促和分子建模方法来确定酰基链和极性头部修饰对 NAAA 底物识别和水解的影响。结果表明,在饱和和单不饱和 FAE 中,催化效率严格取决于脂肪酰基链长,而对极头的修改有更广泛的容忍度。这种关系反映了酶-底物复合物在分子动力学模拟中的相对稳定性。

更新日期:2021-07-14
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