The role of human monoacylglycerol lipase (hMAGL) binding pocket in breakup of unsaturated phospholipid membranes

Published

November 1, 2017

Author(s)

Ioannis L. Karageorgos, Vitalii I. Silin, nikolai zvonok, John P. Marino, David Janero, Alexandros Makriyannis

Abstract

Human monoacylglycerol lipase (hMAGL) plays a key role in homeostatic tuning of the endocannabinoid signaling system and supports aggressive tumorogenesis, making this enzyme a promising therapeutic target. hMAGL features a membrane-associated lid domain that regulates entry of endocannabinoid lipid substrates into the hydrophobic channel accessing the active site, likely from the membrane bilayer. The present work applied simultaneous surface plasmon resonance and electrochemical impedance spectroscopy measurements to show that, in absence of the substrate, hMAGL can remove phospholipid molecules from the membrane and, thereby, disintegrate pre-formed, intact, tethered phospholipid bilayer membrane mimetics (tBLMs) composed of unsaturated phosphatidylcholines. To probe the mechanism of hMAGL-induced on tBLMs compromise, we investigated the effect of wild type and mutant hMAGLs and hMAGL rendered catalytically inactive, as a function of concentration and in the presence of chemically distinct active-site inhibitors. Our data show that hMAGL's lid domain and hydrophobic substrate-binding pocket play important roles in hMAGL-induced bilayer lipid mobilization, whereas hydrolytic activity of the enzyme does not appear to be a factor.

Citation

Analytical Biochemistry

Volume

536

Pub Type

Journals

Download Paper

DOI Link

Keywords

Electrochemical impedance spectroscopy (EIS), Human monoacylglycerol lipase (hMAGL), Surface plasmon resonance (SPR), Tethered lipid bilayer membrane (tBLM).

Citation

Karageorgos, I. , Silin, V. , Zvonok, N. , Marino, J. , Janero, D. and Makriyannis, A. (2017), The role of human monoacylglycerol lipase (hMAGL) binding pocket in breakup of unsaturated phospholipid membranes, Analytical Biochemistry, [online], https://doi.org/10.1016/j.ab.2017.08.009 (Accessed October 10, 2025)