NDLI: Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism

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Molecular BioSystems Vol - 6 Issue - 7

Molecular BioSystems Vol - 6 Issue - 6

Molecular BioSystems Vol - 6 Issue - 5

Molecular BioSystems Vol - 6 Issue - 4

Molecular BioSystems Vol - 6 Issue - 3

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Molecular BioSystems Vol -2

Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism

Content Provider	Royal Society of Chemistry (RSC)
Author	Tyukhtenko, Sergiy Sallum, Christine Zvonok, Nikolai Karageorgos, Ioannis Makriyannis, Alexandros Janero, David R.
Copyright Year	2010
Abstract	Intramolecular hydrogen bonding is an important determinant of enzyme structure, catalysis, and inhibitor action. Monoacylglycerol lipase (MGL) modulates cannabinergic signaling as the main enzyme responsible for deactivating 2-arachidonoylglycerol (2-AG), a primary endocannabinoid lipid messenger. By enhancing tissue-protective 2-AG tone, targeted MGL inhibitors hold therapeutic promise for managing pain and treating inflammatory and neurodegenerative diseases. We report study of purified, solubilized human MGL (hMGL) to explore the details of hMGL catalysis by using two known covalent hMGL inhibitors, the carbamoyl tetrazole AM6701 and N-arachidonoylmaleimide (NAM), that act through distinct mechanisms. Using proton nuclear magnetic resonance spectroscopy (NMR) with purified wild-type and mutant hMGLs, we have directly observed a strong hydrogen-bond network involving Asp239 and His269 of the catalytic triad and neighboring Leu241 and Cys242 residues. hMGL inhibition by AM6701 alters this hydrogen-bonding pattern through subtle active-site structural rearrangements without influencing hydrogen-bond occupancies. Rapid carbamoylation of hMGL Ser122 by AM6701 and elimination of the leaving group is followed by a slow hydrolysis of the carbamate group, ultimately regenerating catalytically competent hMGL. In contrast, hMGL titration with NAM, which leads to cysteine alkylation, stoichiometrically decreases the population of the active-site hydrogen bonds. NAM prevents reformation of this network, and in this manner inhibits hMGL irreversibly. These data provide detailed molecular insight into the distinctive mechanisms of two covalent hMGL inhibitors and implicate a hydrogen-bond network as a structural feature of hMGL catalytic function.
Starting Page	1381
Ending Page	1388
Page Count	8
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	6
Issue Number	8
Journal	Molecular BioSystems
DOI	10.1039/c004515b
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Cysteine Enzyme Determinant Enzyme inhibitor Cannabinoidergic 2-Arachidonoylglycerol Nuclear magnetic resonance spectroscopy Proton nuclear magnetic resonance Lipid Hydrolysis Endocannabinoid system Monoacylglycerol lipase Catalytic triad Tetrazole Covalent bond Titration NAM Nuclear magnetic resonance Mutation Leaving group Carbamate Hydrogen bond
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism †

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Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism

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Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism †

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Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism