Specific Inter-residue Interactions as Determinants of Human Monoacylglycerol Lipase Catalytic Competency: A ROLE FOR GLOBAL CONFORMATIONAL CHANGES.

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TitleSpecific Inter-residue Interactions as Determinants of Human Monoacylglycerol Lipase Catalytic Competency: A ROLE FOR GLOBAL CONFORMATIONAL CHANGES.
Publication TypeJournal Article
Year of Publication2016
AuthorsTyukhtenko, S, Karageorgos, I, Rajarshi, G, Zvonok, N, Pavlopoulos, S, Janero, DR, Makriyannis, A
JournalJ Biol Chem
Volume291
Issue6
Pagination2556-65
Date Published2016 Feb 5
ISSN1083-351X
Abstract

The serine hydrolase monoacylglycerol lipase (MGL) functions as the main metabolizing enzyme of 2-arachidonoyl glycerol, an endocannabinoid signaling lipid whose elevation through genetic or pharmacological MGL ablation exerts therapeutic effects in various preclinical disease models. To inform structure-based MGL inhibitor design, we report the direct NMR detection of a reversible equilibrium between active and inactive states of human MGL (hMGL) that is slow on the NMR time scale and can be modulated in a controlled manner by pH, temperature, and select point mutations. Kinetic measurements revealed that hMGL substrate turnover is rate-limited across this equilibrium. We identify a network of aromatic interactions and hydrogen bonds that regulates hMGL active-inactive state interconversion. The data highlight specific inter-residue interactions within hMGL modulating the enzymes function and implicate transitions between active (open) and inactive (closed) states of the hMGL lid domain in controlling substrate access to the enzymes active site.

DOI10.1074/jbc.M115.670257
Alternate JournalJ. Biol. Chem.
PubMed ID26555264
PubMed Central IDPMC4742725