期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 36, 期 1, 页码 1411-1423出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.1912035
关键词
N-acylethanolamine acid amidase; palmitoylethanolamide; substrate selectivity; enzyme kinetic; molecular dynamics
资金
- Italian Ministry for University and Research [MIUR] [20175SA5JJ]
- National Institute of Health [1RF1AG065329-01A1]
- Programme FIL-Quota Incentivante of University of Parma
- Fondazione Cariparma
The catalytic efficiency of NAAA is strictly dependent on the length of the fatty acyl chain in both saturated and monounsaturated FAEs, with a wider tolerance for modifications of the polar heads. This relationship is reflective of the relative stability of enzyme-substrate complexes in molecular dynamics simulations.
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.
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