Sandbox Reserved 919: Difference between revisions
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==Introduction== | ==Introduction== | ||
'''Monoglyceride Lipase''' ('''MGL''', '''MAGL''', '''MGLL''') is a 33 kDa [http://en.wikipedia.org/wiki/Protein protein] <ref name="labar"> PMID:19957260 </ref> found mostly in the cell membrane. MGL is a [http://en.wikipedia.org/wiki/Serine_hydrolase serine hydrolase] enzyme that contains an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold]. MGL plays a key role in the hydrolysis of [http://en.wikipedia.org/wiki/2-Arachidonoylglycerol 2-arachidonoylglycerol] (2-AG), an endocannabinoid produced by the the central nervous system.<ref name="labar" /><ref name="bert"> PMID:19962385 </ref><ref name="shalk"> PMID:21308848 </ref><ref name="blank"> PMID:18096503 </ref> The hydrolase fold, along with a characteristic [http://en.wikipedia.org/wiki/Amphiphile amphipathic] occluded tunnel, allows 2-AG to selectively bind to the active site of MGL and be degraded into [http://en.wikipedia.org/wiki/Arachidonic_acid arachidonic acid] and glycerol. 2-AG has been found to possess anti-nociceptive, immunomodulatory, anti-inflammatory and tumor-reductive character when it binds to cannabinoid receptors. <ref name="labar" /> <ref name="bert"/> Due to the vast medical and therapeutic utility of 2-AG, the inhibition of MGL is a high interest target in pharmaceutical research. Furthermore, MGL has also been cited as having both negative and positive effector roles in cancer pathology. <ref name="nomura"> PMID:21802006 </ref> <ref name="hong"> PMID:22349814 </ref> | '''Monoglyceride Lipase''' ('''MGL''', '''MAGL''', '''MGLL''') is a 33 kDa [http://en.wikipedia.org/wiki/Protein protein] <ref name="labar"> PMID:19957260 </ref> found mostly in the cell membrane <scene name='57/573133/Generic_monomer/3'>(default view)</scene>. MGL is a [http://en.wikipedia.org/wiki/Serine_hydrolase serine hydrolase] enzyme that contains an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold]. MGL plays a key role in the hydrolysis of [http://en.wikipedia.org/wiki/2-Arachidonoylglycerol 2-arachidonoylglycerol] (2-AG), an endocannabinoid produced by the the central nervous system.<ref name="labar" /><ref name="bert"> PMID:19962385 </ref><ref name="shalk"> PMID:21308848 </ref><ref name="blank"> PMID:18096503 </ref> The hydrolase fold, along with a characteristic [http://en.wikipedia.org/wiki/Amphiphile amphipathic] occluded tunnel, allows 2-AG to selectively bind to the active site of MGL and be degraded into [http://en.wikipedia.org/wiki/Arachidonic_acid arachidonic acid] and glycerol. 2-AG has been found to possess anti-nociceptive, immunomodulatory, anti-inflammatory and tumor-reductive character when it binds to cannabinoid receptors. <ref name="labar" /> <ref name="bert"/> Due to the vast medical and therapeutic utility of 2-AG, the inhibition of MGL is a high interest target in pharmaceutical research. Furthermore, MGL has also been cited as having both negative and positive effector roles in cancer pathology. <ref name="nomura"> PMID:21802006 </ref> <ref name="hong"> PMID:22349814 </ref> | ||
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<StructureSection load='3PE6' size='300' frame='true' align='right' caption= 'Structure' scene='57/573133/Generic_monomer/3'> | <StructureSection load='3PE6' size='300' frame='true' align='right' caption= 'Structure' scene='57/573133/Generic_monomer/3'> | ||
===3D Structure=== | ===3D Structure=== | ||
The first crystal structure of MGL was determined in 2009 | The first complete crystal structure of MGL was determined in 2009 in its apo form. <ref name="bert" /> MGL is a part of the α-β hydrolase family of enzymes.<ref name="labar" /><ref name="bert" /><ref name="shalk" /> This category of proteins contains an <scene name='57/573134/Beta_sheet/1'>eight-stranded</scene> [http://en.wikipedia.org/wiki/Beta_sheet beta sheet], specifically containing seven parallel and one antiparallel constituent strand, surrounded by [http://en.wikipedia.org/wiki/Alpha_helix alpha-helices]. <ref name="bert" /> | ||
MGL has a characteristic lid domain comprised of two large loops that surround <scene name='57/573134/Helix_a4/1'>helix A4</scene>.<ref name="bert" /> This region of the enzyme is the membrane-interacting moiety of the protein, which is consistent with its [http://en.wikipedia.org/wiki/Amphiphile amphipathic] nature and outward-facing hydrophobic residues. 2-AG and other lipids suspended in the hydrophobic section of the cell membrane have been proposed to associate with this region of MGL before entering the active tunnel. Interestingly, MGL’s lid domain may be more flexible than its analogs in other α-β hydrolases, due to the various conformations it assumed in [http://en.wikipedia.org/wiki/Crystallography crystallographic studies]. <ref name="bert" /> Currently, there is no consensus regarding the quaternary arrangement of MGL. Some studies show that MGL is primarily found as a [http://en.wikipedia.org/wiki/Monomer monomer], <ref name="bert" /> <ref name="shalk" /> whereas other studies have found it to be a physiologically active <scene name='57/573134/Dimer/1'>dimer</scene>. <ref name="labar" /> One compelling piece of evidence for the dimeric quartenary structure is the presence of a perfectly aligned pair of beta strands between the two molecules of MGL in [http://www.rcsb.org/pdb/explore.do?structureId=3jw8 3JW8]. | MGL has a characteristic lid domain comprised of two large loops that surround <scene name='57/573134/Helix_a4/1'>helix A4</scene>.<ref name="bert" /> This region of the enzyme is the membrane-interacting moiety of the protein, which is consistent with its [http://en.wikipedia.org/wiki/Amphiphile amphipathic] nature and outward-facing hydrophobic residues. 2-AG and other lipids suspended in the hydrophobic section of the cell membrane have been proposed to associate with this region of MGL before entering the active tunnel. Interestingly, MGL’s lid domain may be more flexible than its analogs in other α-β hydrolases, due to the various conformations it assumed in [http://en.wikipedia.org/wiki/Crystallography crystallographic studies]. <ref name="bert" /> Currently, there is no consensus regarding the quaternary arrangement of MGL. Some studies show that MGL is primarily found as a [http://en.wikipedia.org/wiki/Monomer monomer], <ref name="bert" /> <ref name="shalk" /> whereas other studies have found it to be a physiologically active <scene name='57/573134/Dimer/1'>dimer</scene>. <ref name="labar" /> One compelling piece of evidence for the dimeric quartenary structure is the presence of a perfectly aligned pair of beta strands between the two molecules of MGL in [http://www.rcsb.org/pdb/explore.do?structureId=3jw8 3JW8]. | ||