Sandbox reserved 915: Difference between revisions
No edit summary |
No edit summary |
||
| (9 intermediate revisions by the same user not shown) | |||
| Line 3: | Line 3: | ||
[[Image:Complete_crystal_structure.png|left|300px|thumb|'''Figure 1:'''Crystal Structure of MGL Alpha helixes are in blue and beta sheets in purple. This protein is a dimer that is linked by antiparallel beta sheets]] | [[Image:Complete_crystal_structure.png|left|300px|thumb|'''Figure 1:'''Crystal Structure of MGL Alpha helixes are in blue and beta sheets in purple. This protein is a dimer that is linked by antiparallel beta sheets]] | ||
==Background== | ==Background== | ||
Monoglyceride [[:Category:Lipase| Lipase]] (MGL) is part of the α/β hydrolase family,a [[:Category:Serine hydrolase| Serine hydrolase]] | Monoglyceride [[:Category:Lipase| Lipase]] (MGL) is part of the α/β hydrolase family,a [[:Category:Serine hydrolase| Serine hydrolase]] '''Figure 1''', having a <scene name='58/580298/Catalytic_triad/4'>Ser-His-Asp catalytic triad </scene> <ref name="Clemente">[Clemente, J. C., E. Nulton, M. Nelen, M. J. Todd, D. Maguire, C. Schalk-Hihi, L. C. Kuo, S.-P. Zhang, C. M. Flores, and J. K. Kranz. "Screening and Characterization of Human Monoglyceride Lipase Active Site Inhibitors Using Orthogonal Binding and Functional Assays." Journal of Biomolecular Screening 17.5 (2012): 629-40]</ref>. [http://en.wikipedia.org/wiki/Monoacylglycerol_lipase MGL] is present in most cells, providing the rate limiting step for the hydrolysis of [http://en.wikipedia.org/wiki/Monoglyceride monoacylglycerols] (MG) into fatty acids and glycerol <ref name="Taschler">[Taschler, U., F. P. W. Radner, C. Heier, R. Schreiber, M. Schweiger, G. Schoiswohl, K. Preiss-Landl, D. Jaeger, B. Reiter, H. C. Koefeler, J. Wojciechowski, C. Theussl, J. M. Penninger, A. Lass, G. Haemmerle, R. Zechner, and R. Zimmermann. "Monoglyceride Lipase Deficiency in Mice Impairs Lipolysis and Attenuates Diet-induced Insulin Resistance." Journal of Biological Chemistry 286.20 (2011): 17467-7477]</ref> . MGL also terminates the signaling of a primary endocannabinoid, 2-arachidonoyl glycerol (2-AG) <ref name="Savinainen">[Savinainen, Juha R., Megumi Yoshino, Anna Minkkilä, Tapio Nevalainen, and Jarmo T. Laitinen. "Characterization of Binding Properties of Monoglyceride Lipase Inhibitors by a Versatile Fluorescence-based Technique." Analytical Biochemistry 399.1 (2010): 132-34]</ref>. MGL is the main enzyme responsible for hydrolyzing 2-arachidonoylglycerol into arachidonic acid and glycerol ''in vivo'' '''Figure 3''' <ref name="Bertrand">[ Bertrand, T., F. Augé, J. Houtmann, A. Rak, F. Vallée, V. Mikol, P.f. Berne, N. Michot, D. Cheuret, C. Hoornaert, and M. Mathieu. "Structural Basis for Human Monoglyceride Lipase Inhibition." Journal of Molecular Biology 396.3 (2010): 663-73.]</ref>. One of the key features of MGL is the hydrophobic tunnel, which has been suggested to provide a model for drug research '''Figure 7'''. <ref name="Bertrand" /> | ||
===Metabolic Role=== | ===Metabolic Role=== | ||
Monoglyceride | Monoglyceride Lipase is involved in energy metabolism through two mechanisms. In the first mechanism of energy metabolism, MGL is able to hydrolyze monoacylglycerols into fatty acids and glycerol, which are able to then be used for energy production <ref name="Taschler" />. The second mechanism involves the degradation of 2-arachidonoyl glycerol (2-AG), which is a common endogenous ligand of cannabinoid receptors, by MGL. Looking ''in vivo'' of the metabolic role of MGL, MGL deficient mice showed increased monoacylglycerols in adipose tissue, brain, and liver as well as elevated 2-AG levels. With defective MGL, lipolysis is debilitated and diet-induced insulin resistance is reduced <ref name="Taschler" />. | ||
===Component of Endocannabinoid System=== | ===Component of Endocannabinoid System=== | ||
MGL degrades [http://en.wikipedia.org/wiki/2-Arachidonoylglycerol 2-Arachidonoylglycerol | MGL also degrades [http://en.wikipedia.org/wiki/2-Arachidonoylglycerol 2-Arachidonoylglycerol] (2-AG), an [http://books.google.com/booksid=BxfLB4n3uoMC&pg=PA34&lpg=PA34&dq=hydrolysis+of+2-AG+by+MGL&source=bl&ots=R6Xm0KgGdK&sig=K3AwwtDNxbNUKJoa3zsd_25wVKs&hl=en&sa=X&ei=yOI5U43kCcbUsAT9_4DoBw&ved=0CGEQ6AEwCg#v=onepage&q=hydrolysis%20of%202-AG%20by%20MGL&f=false endocannabinoid], | ||
. In the brain endocannabinoids are released from postsynaptic neurons, causing the retrograde suppression of synaptic transmission. | to a glycerol and arachidonic acid. <ref name="Clemente"/> In the brain, endocannabinoids (ECs)are released from postsynaptic neurons, causing the retrograde suppression of synaptic transmission. <ref name="Taschler"/> | ||
In | In peripheral tissues, endocannabinoids (ECs) are active in autonomic nervous system. EC signalling affects processes such as learning, motor control, cognition, and pain <ref name="Taschler" />. EC signalling is also able to regulate lipid metabolism and food intake. Looking at the role of MGL in energy metabolism, a deficiency in MGL in animals led to the buildup of 2-AG <ref name="Taschler" />. The endocannabinoid 2-AG has a nociceptive effect in pain signalling <ref name="Clemente" />. MGL degrades 2-AG, preventing 2-AG from remaining bound to the cannabinoid receptor and therefore terminating the pain signal. Without the degradation of 2-AG by MGL, 2-AG levels would increase which would lead to a prolonged nociceptive effect <ref name="Clemente" /> | ||
===Inhibition of MGL=== | ===Inhibition of MGL=== | ||
| Line 28: | Line 28: | ||
==Structure== | ==Structure== | ||
The <scene name='58/580298/Overall_structure/3'>overall structure</scene> of MGL has an eight-stranded β-sheet protein fold with seven parallel and one <scene name='58/580299/Beta_sheets/1'> antiparallel strand </scene>. Similar to the other α/β hydrolases, the β-sheets in the center of the protein surrounded by α-helices. The combination of the α-helices and β-sheets are able to provide a stable scaffold for the active site within MGL. MGL is monomeric. The catalytic triad, containing Ser132, His279, and Asp249, is found at the bottom of the binding pocket <ref name="Bertrand" />. | |||
MGL has eight-stranded β-sheet protein fold with seven parallel and one <scene name='58/580299/Beta_sheets/1'> antiparallel strand </scene>. | |||
== Catalytic triad == | == Catalytic triad == | ||
| Line 49: | Line 48: | ||
==Ligand Binding Site== | ==Ligand Binding Site== | ||
[[Image:Overall_ligand.png|left|200px|thumb|'''Figure 6:''' Ligand within the Overall Structure of MGL]] | [[Image:Overall_ligand.png|left|200px|thumb|'''Figure 6:''' Ligand within the Overall Structure of MGL]] [[Image:Ligand_tunnel.png|right|200px|thumb|'''Figure 7:''' Ligand binding pocket showing the hydrophobic and polar regions]] | ||
The <scene name='58/580298/Ligand/1'>ligand binding pocket</scene> of MGL has a large hydrophobic region with a polar bottom. The entrance of the binding pocket for MGL contains a lid, which is very flexible. The binding pocket or tunnel within MGL matches with the overall structure of 2-AG, with 2-AG's polar head being cleaved by the catalytic triad. | The <scene name='58/580298/Ligand/1'>ligand binding pocket</scene> of MGL has a large hydrophobic region with a polar bottom. The entrance of the binding pocket for MGL contains a lid, which is very flexible <ref name="Bertrand" />. The binding pocket or tunnel within MGL matches with the overall structure of 2-AG, with 2-AG's polar head being cleaved by the catalytic triad '''Figure 7'''. The binding pocket is not being adjusted to the ligand's shape. However, the main movements of MGL involve the lid region of the ligand binding pocket upon the ligand binding. When 2-AG and its isomer 1(3)-AG bind to MGL, the hydrophobic chain is first aligned with the left part of the binding pocket. The carbonyl on 2-AG and 1(3)-AG is then hydrogen bonded to <scene name='58/580298/Ala61/1'>Ala61</scene>. The polar head group of the ligand is then fixed by three hydrogen bonds. The large lipophilic portion of the binding pocket is being used to design more selectivie inhibitors <ref name="Bertrand" />. | ||
== References == | == References == | ||