title: Specific Inter-residue Interactions as Determinants of Human Monoacylglycerol Lipase Catalytic Competency: A ROLE FOR GLOBAL CONFORMATIONAL CHANGES.
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.
authors.affiliation: From the Center for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000 and.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Tyukhtenko
authors.affiliation: From the Center for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000 and.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karageorgos
authors.affiliation: From the Center for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000 and.
authors.forename: Girija
authors.initials: G
authors.lastname: Rajarshi
authors.affiliation: From the Center for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000 and.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Zvonok
authors.affiliation: From the Center for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000 and.
authors.forename: Spiro
authors.initials: S
authors.lastname: Pavlopoulos
authors.affiliation: From the Center for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000 and.
authors.forename: David R
authors.initials: DR
authors.lastname: Janero
authors.affiliation: From the Center for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000 and King Abdulaziz University, Jeddah, 22254, Saudi Arabia a.makriyannis@neu.edu.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008994:Monoacylglycerol Lipases / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D008994:Monoacylglycerol Lipases
keywords: catalytic efficiency; conformational change; lipase; nuclear magnetic resonance (NMR); serine protease; spectroscopy