Specific Inter-residue Interactions as Determinants of Human Monoacylglycerol Lipase Catalytic Competency
| Autor: | David R. Janero, Spiro Pavlopoulos, Alexandros Makriyannis, Nikolai Zvonok, Sergiy Tyukhtenko, Girija Rajarshi, Ioannis Karageorgos |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Serine protease Conformational change 030102 biochemistry & molecular biology biology Active site Serine hydrolase Cell Biology Biochemistry Monoacylglycerol lipase 03 medical and health sciences 030104 developmental biology Enzyme chemistry biology.protein Structure–activity relationship Lipase Molecular Biology |
| Zdroj: | Journal of Biological Chemistry. 291:2556-2565 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m115.670257 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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