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=Monoglyceride Lipase= | =Monoglyceride Lipase= | ||
[[Image: | [[Image:MGLpic.png|150 px|right|thumb|Figure 1: Monomer of MGL created in PYMOL [http://www.rcsb.org/pdb/explore/explore.do?structureId=3pe6 (PDB:3PE6)], colored by surface electrostatic potential (blue as positive, red as negative).]] | ||
==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 (<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 | '''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 MGL's active site to selectively bind to 2-AG and [http://www.biologie.uni-freiburg.de/data/bio2/schroeder/Chemical_Structures/Anandamide.gif degrade it] into [http://en.wikipedia.org/wiki/Arachidonic_acid arachidonic acid] and glycerol.<ref name="bert" /> 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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==Structure== | ==Structure== | ||
<StructureSection load='3PE6' size='300' | <StructureSection load='3PE6' size='300' side='right' caption= 'Structure' scene='57/573133/Generic_monomer/3'> | ||
===3D Structure=== | ===3D Structure=== | ||
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/6'>eight-stranded</scene> [http://en.wikipedia.org/wiki/Beta_sheet beta sheet], specifically containing seven parallel and one antiparallel constituent strand, <scene name='57/573134/Beta_sheet/5'>surrounded</scene> by [http://en.wikipedia.org/wiki/Alpha_helix alpha-helices]. <ref name="bert" /> | 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/6'>eight-stranded</scene> [http://en.wikipedia.org/wiki/Beta_sheet beta sheet], specifically containing seven parallel and one antiparallel constituent strand, <scene name='57/573134/Beta_sheet/5'>surrounded</scene> by [http://en.wikipedia.org/wiki/Alpha_helix alpha-helices]. <ref name="bert" /> | ||
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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" /> | 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]; cysteine-reactive inhibitors such as [http://www.chemspider.com/Chemical-Structure.24774833.html N-arachidonoylmaleimide] (NAM); and irreversible serine-reactive inhibitors such as [http://en.wikipedia.org/wiki/JZL184 JZL184] and <scene name='57/573134/Sar629/3'>SAR 629</scene>.<ref name="bert" /> SAR629 | 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]; cysteine-reactive inhibitors such as [http://www.chemspider.com/Chemical-Structure.24774833.html N-arachidonoylmaleimide] (NAM); and irreversible serine-reactive inhibitors such as [http://en.wikipedia.org/wiki/JZL184 JZL184] and <scene name='57/573134/Sar629/3'>SAR 629</scene>.<ref name="bert" /> SAR629 covalently binds to the catalytic Serine-132; the oxygen of the nucleophilic serene residue attacks the carbonyl carbon of SAR629, forming a [http://en.wikipedia.org/wiki/Carbamate carbamate]. This covalent bond is believed to be reversible via hydrolysis, albeit slowly.<ref name="bert" /> Due to JZL184's similar structure to SAR629, it may undergo a similar reaction with MGL.<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" /> | ||
</StructureSection> | </StructureSection> | ||