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. 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" | '''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="bert"> PMID:19962385 </ref><ref name="labar" /><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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The first crystal structure of MGL was determined in 2009, complete in its <scene name='57/573133/Generic_monomer/3'>apo form</scene>. <ref name="bert" /> MGL is a part of the α-β hydrolase family of enzymes. 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" /> | The first crystal structure of MGL was determined in 2009, complete in its <scene name='57/573133/Generic_monomer/3'>apo form</scene>. <ref name="bert" /> MGL is a part of the α-β hydrolase family of enzymes. 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>. 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 monomer, <ref name="bert" /> <ref name="shalk" | MGL has a characteristic lid domain comprised of two large loops that surround <scene name='57/573134/Helix_a4/1'>helix A4</scene>. 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 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 based on the presence of a continuous, helical arrangement of beta sheets that suggests favorable dimeric interaction. | ||
===Active Site=== | ===Active Site=== | ||
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2-AG activates the same cannabinoid receptors (CB1 and CB2) for both [http://en.wikipedia.org/wiki/Anandamide anandamide] and the main psychoactive compound found in Cannabis sativa, [http://en.wikipedia.org/wiki/Tetrahydrocannabinol Δ9-Tetrahydrocannabinol] (THC), via [http://en.wikipedia.org/wiki/Retrograde_signaling retrograde signaling]. <ref name="bert" /> 2-AG is the most abundant endocannabinoid found in the brain, possessing analgesic, anti-inflammatory, immunomodulating, neuroprotective, and hypotensive effects.<ref name="labar" /><ref name="nomura" /> | 2-AG activates the same cannabinoid receptors (CB1 and CB2) for both [http://en.wikipedia.org/wiki/Anandamide anandamide] and the main psychoactive compound found in Cannabis sativa, [http://en.wikipedia.org/wiki/Tetrahydrocannabinol Δ9-Tetrahydrocannabinol] (THC), via [http://en.wikipedia.org/wiki/Retrograde_signaling retrograde signaling]. <ref name="bert" /> 2-AG is the most abundant endocannabinoid found in the brain, possessing analgesic, anti-inflammatory, immunomodulating, neuroprotective, and hypotensive effects.<ref name="labar" /><ref name="nomura" /> | ||
Approximately 85% of the 2-AG in the rat brain is metabolized by MGL, while other lipases such as [http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase fatty acid amide hydrolase] (FAAH) process the remainder of the metabolite. <ref name="blank" | Approximately 85% of the 2-AG in the rat brain is metabolized by MGL, while other lipases such as [http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase fatty acid amide hydrolase] (FAAH) process the remainder of the metabolite.<ref name="blank" /> Based on these studies, MGL has been assigned as the primary enzyme for the metabolism of 2-AG in humans, making it a highly desirable target enzyme for the modulation of 2-AG concentration in the body. <ref name="labar" /><ref name="bert" /><ref name="shalk" /> Although the most-studied role of MGL is the degradation of 2-AG in the brain, MGL may also play a role in adipose tissue, completing the hydrolysis of triglycerides into fatty acids and glycerol, as well as working in the liver to mobilize triglycerides for secretion. <ref name="labar" /><ref name="shalk" /> | ||
===MGL Inhibitors=== | ===MGL Inhibitors=== | ||
Three general MGL [http://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitor] classes have been observed: noncompetitive, partially irreversible inhibitors such as [http://en.wikipedia.org/wiki/URB602 URB602]; irreversible serine-reactive inhibitors such as [http://en.wikipedia.org/wiki/JZL184 JZL184] and <scene name='57/573134/Sar629/1'>SAR 629</scene>; and cysteine-reactive inhibitors such as [http://www.chemspider.com/Chemical-Structure.24774833.html N-arachidonoylmaleimide] (NAM). <ref name="bert" /> Despite the existence of multiple lead compounds, there is a strong demand for the creation of more highly-specific and more potent inhibitors that could be used as anti-pain drugs for their ability to keep 2-AG active in the neuronal synapses. <ref name="labar" /> | Three general MGL [http://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitor] classes have been observed: noncompetitive, partially irreversible inhibitors such as [http://en.wikipedia.org/wiki/URB602 URB602]; irreversible serine-reactive inhibitors such as [http://en.wikipedia.org/wiki/JZL184 JZL184] and <scene name='57/573134/Sar629/1'>SAR 629</scene>; and cysteine-reactive inhibitors such as [http://www.chemspider.com/Chemical-Structure.24774833.html N-arachidonoylmaleimide] (NAM). <ref name="bert" /> Despite the existence of multiple lead compounds, there is a strong demand for the creation of more highly-specific and more potent inhibitors that could be used as anti-pain drugs for their ability to keep 2-AG active in the neuronal synapses. <ref name="labar" /> | ||