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=Monoglyceride Lipase=

[[Image:MGLProt.jpg|150 px|right|thumb|Figure 1: Monomer of MGL created in PYMOL (PDB:3PE6), colored by secondary structure.]]
==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 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.<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==
<StructureSection load='3PE6' size='300' frame='true' align='right' caption= 'Structure' scene='57/573133/Generic_monomer/3'>
===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" />

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 <scene name='57/573134/Helix_a4/2'>hydrophobic residues</scene> (graphite being nonpolar and cyan being highly polar). 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.<ref name="bert" /> 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 <scene name='57/573134/Beta_strand_pair/5'>precisely aligned</scene> pair of beta strands between the two molecules of MGL in [http://www.rcsb.org/pdb/explore.do?structureId=3jw8 3JW8].

===Active Site===
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===
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" />


==Biological/Medical Relevance==
===2-AG Metabolism===
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" /><ref name="labar" /> 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" /> 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===
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 is covalently bound to the catalytic Serine-132; the oxygen of the nucleophilic serene residue attacks a 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> 

==Cancer Research==
MGL is also a target for continuing cancer research, with the potential to help distinguish the role of fatty acids in [http://en.wikipedia.org/wiki/Malignancy malignancy]. Also of interest is the varying efficacy of endocannabinoids as anti-cancer agents in different body tissues and the multifarious influences on the PI-3k/Akt signaling pathway in [http://en.wikipedia.org/wiki/Carcinogenesis carcinogenesis]. <ref name="hong" />

MGL exerts a twofold influence on cancer growth; endocannabinoids such as 2-AG have been shown to have anti-tumorigenic properties <ref name="labar" /> <ref name="nomura" /> and a high fatty-acid concentration may play a role in the promotion of cancer aggressiveness and malignancy. In aggressive breast, melanoma, ovarian, and prostate cancer cells, MGL activity was found to be higher than in nonaggressive malignant cells.<ref name="nomura" /> Subsequently, the creation of effective MGL inhibitors may help to treat highly aggressive cancers in addition to their proposed use as analgesics. 

Recent evidence, however, has suggested that in lung, breast, ovary, stomach, and colorectal cancer, MGL expression was reduced. In addition to controlling 2-AG degradation and fatty acid synthesis pathways, MGL also interacts with key phospholipids (specifically, the 3-phosphorylated phosphoinositide products of PI-3K) in the [http://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway PI3K/Akt signaling and tumor growth pathway]. MGL serves as a negative effector in the pathway: as the concentration of MGL decreases, [http://en.wikipedia.org/wiki/AKT Akt] phosphorylation increases. <ref name= "hong" />

MGL’s role in different body tissues is an ongoing area of research aimed at elucidating its complex role in cancer pathology. MGL’s effect on exogenous cannabinoid medications that are administered to cancer patients as a palliative medication is of particular scientific interes. <ref name="nomura" />


==References==
{{reflist}}