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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'> | '''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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===Active Site=== | ===Active Site=== | ||
MGL contains an active site tunnel roughly 25Å long and 8Å wide residing beneath its lid region. Like its substrates, 2-AG and other [http://en.wikipedia.org/wiki/Monoglyceride monoacylglycerols], the tunnel is largely amphipathic. Hydrophobic residues dominate the tunnel with the exception of the terminal occluded region, which houses the [http://en.wikipedia.org/wiki/Catalytic_triad#Ser-His-Asp catalytic triad]. In its apo form, the catalytic region is not solvent-exposed, unlike the wide opening of the tunnel. <ref name="labar" /><ref name="bert" /> A unique structural motif in MGL is a 5Å solvent-exposed hole connecting the exterior to the catalytic site. This structure is proposed to act as an “exit hole” through which the glycerol product leaves MGL. The fatty acid product, namely arachidonic acid, presumably travels back through the active site tunnel. <ref name="labar" /><ref name="bert" /><ref name="shalk" /> | MGL contains an active site | ||
<scene name='57/573134/Active_tunnel/1'>tunnel</scene> roughly 25Å long and 8Å wide residing beneath its lid region. Like its substrates, 2-AG and other [http://en.wikipedia.org/wiki/Monoglyceride monoacylglycerols], the tunnel is largely amphipathic. Hydrophobic residues dominate the tunnel with the exception of the terminal occluded region, which houses the [http://en.wikipedia.org/wiki/Catalytic_triad#Ser-His-Asp catalytic triad]. In its apo form, the catalytic region is not solvent-exposed, unlike the wide opening of the tunnel. <ref name="labar" /><ref name="bert" /> A unique structural motif in MGL is a 5Å solvent-exposed hole connecting the exterior to the catalytic site. This structure is proposed to act as an “exit hole” through which the glycerol product leaves MGL. The fatty acid product, namely arachidonic acid, presumably travels back through the active site tunnel. <ref name="labar" /><ref name="bert" /><ref name="shalk" /> | |||
===Catalytic Triad=== | ===Catalytic Triad=== | ||
MGL’s serine hydrolase chemistry is executed by a <scene name='57/573134/Catalytic_triad/ | MGL’s serine hydrolase chemistry is executed by a <scene name='57/573134/Catalytic_triad/4'>Catalytic Triad</scene> (Ser132-His279-Asp249) and seems to utilize the same mechanism as the much-studied [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin]. In this mechanism, an activated serine nucleophile cleaves the ester bond of the substrate.<ref name="labar" /><ref name="bert" /><ref name="shalk" /> The subsequent tetrahedral intermediate is stabilized by the <scene name='57/573134/Oxyanion_hole/3'>Oxyanion Hole</scene>, formed by the main-chain nitrogens of Ala61 and Met (or Se-Met) 133.<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]; irreversible serine-reactive inhibitors such as [http://en.wikipedia.org/wiki/JZL184 JZL184] and <scene name='57/573134/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> | ||