Monoglyceride lipase: Difference between revisions
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<StructureSection load='' size=' | {{BAMBED | ||
|DATE=June 4, 2014 | |||
|OLDID=1939273 | |||
|BAMBEDDOI=10.1002/bmb.20840 | |||
}} | |||
<StructureSection load='' size='350' side='right' scene='57/573133/Generic_monomer/3' caption='Monoglyceride Lipase (PDB ID [[3jw8]])'> | |||
==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 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> | '''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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===Catalytic Triad=== | ===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" /> The triad was found using site-directed mutagenesis of each individual residue and each of these amino acid residues are catalytically essential to MGL <ref name=" | 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" /> The triad was found using site-directed mutagenesis of each individual residue and each of these amino acid residues are catalytically essential to MGL <ref name="bert"/>. The catalytic triad is located in the [[:Category:Ligand binding pocket| Binding Pocket]] buried at the bottom of it in the oxyanion hole connected by a water molecule. | ||
===Ligand Binding Site=== | ===Ligand Binding Site=== | ||
[[Image:Overall_ligand.png| | [[Image:Overall_ligand.png|right|200px|thumb|'''Figure 2:''' Ligand within the Overall Structure of MGL]] [[Image:Ligand_tunnel.png|right|200px|thumb|'''Figure 3:''' Ligand binding pocket showing the hydrophobic and polar regions]] | ||
The <scene name='58/580298/Ligand/1'>ligand binding pocket</scene> of MGL has a large hydrophobic region with a polar bottom. The entrance of the binding pocket for MGL contains a lid, which is very flexible <ref name=" | The <scene name='58/580298/Ligand/1'>ligand binding pocket</scene> of MGL has a large hydrophobic region with a polar bottom. The entrance of the binding pocket for MGL contains a lid, which is very flexible <ref name="bert"/>. The binding pocket or tunnel within MGL matches with the overall structure of 2-AG, with 2-AG's polar head being cleaved by the catalytic triad '''Figure 3'''. The binding pocket is not being adjusted to the ligand's shape. However, the main movements of MGL involve the lid region of the ligand binding pocket upon the ligand binding. When 2-AG and its isomer 1(3)-AG bind to MGL, the hydrophobic chain is first aligned with the left part of the binding pocket. The carbonyl on 2-AG and 1(3)-AG is then hydrogen bonded to <scene name='58/580298/Ala61/1'>Ala61</scene>. The polar head group of the ligand is then fixed by three hydrogen bonds. The large lipophilic portion of the binding pocket is being used to design more selectivie inhibitors <ref name="bert"/>. | ||
==Biological/Medical Relevance== | ==Biological/Medical Relevance== | ||
Monoglyceride Lipase is involved in energy metabolism through two mechanisms. In the first mechanism, MGL hydrolyzes monoacylglycerols into fatty acids and glycerol, which are able to then be used for energy production <ref name="Taschler" />. The second mechanism involves the degradation of 2-arachidonoyl glycerol (2-AG), which is a common endogenous ligand of cannabinoid receptors, by MGL. | Monoglyceride Lipase is involved in energy metabolism through two mechanisms. In the first mechanism, MGL hydrolyzes monoacylglycerols into fatty acids and glycerol, which are able to then be used for energy production <ref name="Taschler"> PMID: 21454566 </ref>. The second mechanism involves the degradation of 2-arachidonoyl glycerol (2-AG), which is a common endogenous ligand of cannabinoid receptors, by MGL. | ||
===2-AG Metabolism=== | ===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" /> In the brain, endocannabinoids (ECs) are released from postsynaptic neurons, causing the retrograde suppression of synaptic transmission. <ref name="Taschler"/> In peripheral tissues, endocannabinoids (ECs) are active in autonomic nervous system. EC signalling affects processes such as learning, motor control, cognition, and pain <ref name="Taschler" />. EC signalling is also able to regulate lipid metabolism and food intake. | 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" /> In the brain, endocannabinoids (ECs) are released from postsynaptic neurons, causing the retrograde suppression of synaptic transmission. <ref name="Taschler"/> In peripheral tissues, endocannabinoids (ECs) are active in autonomic nervous system. EC signalling affects processes such as learning, motor control, cognition, and pain <ref name="Taschler" />. EC signalling is also able to regulate lipid metabolism and food intake. | ||
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" /> MGL degrades 2-AG, preventing 2-AG from remaining bound to the cannabinoid receptor and therefore terminating the pain signal. Without the degradation of 2-AG by MGL, 2-AG levels would increase which would lead to a prolonged nociceptive effect <ref name="Clemente" /> 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" /> A deficiency in MGL in animals led to the buildup of 2-AG <ref name="Taschler" />. The endocannabinoid 2-AG has a nociceptive effect in pain signalling <ref name="Clemente" />. 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" /> | 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" /> MGL degrades 2-AG, preventing 2-AG from remaining bound to the cannabinoid receptor and therefore terminating the pain signal. Without the degradation of 2-AG by MGL, 2-AG levels would increase which would lead to a prolonged nociceptive effect <ref name="Clemente"> PMID: 22496098 </ref>. 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" /> A deficiency in MGL in animals led to the buildup of 2-AG <ref name="Taschler" />. The endocannabinoid 2-AG has a nociceptive effect in pain signalling <ref name="Clemente" />. 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 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" />SAR629 adopts a Y shape and interacts with the MGL by hydrophobic interactions, with a few polar interactions as well. '''Figure 4''' [[Image:SAR.png| | 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" />SAR629 adopts a Y shape and interacts with the MGL by hydrophobic interactions, with a few polar interactions as well. '''Figure 4''' [[Image:SAR.png|right|thumb|'''Figure 4:''' The structure and shape of SAR629.]] 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" /> | ||
N-arachidonyl maleimide (NAM) is another inhibitor of MGL. NAM reacts with the amino acid <scene name='58/580298/Cys252/1'>Cys252</scene>. | N-arachidonyl maleimide (NAM) is another inhibitor of MGL. NAM reacts with the amino acid <scene name='58/580298/Cys252/1'>Cys252</scene>. Cys252 is buried in the active site near the catalytic serine and functions by sterically clashing with the natural ligand. A possible conformational change to Cys252 upon the binding of NAM could also lead to an inactive form of MGL. | ||
===Cancer Relevance=== | ===Cancer Relevance=== | ||
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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" /> | 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" /> | ||
==3D structures of monoglyceride lipase== | |||
[[Lipase]] | |||
</StructureSection> | |||
== References == | == References == | ||
<references/> | <references/> | ||
==Similar Proteopedia Pages== | |||
[http://www.proteopedia.org/wiki/index.php/Lipase Lipase] | |||
[http://www.proteopedia.org/wiki/index.php/Lipase_lid_morph Lipase Lid Morph] | |||
[http://www.proteopedia.org/wiki/index.php/Molecular_Playground/Pancreatic_Lipase Pancreatic Lipase] | |||
==Student Contributors== | |||
*Steven Han | |||
*Dominique Stephens | |||
*Erica Yothment | |||
*Greg Zemtsov | |||
[[Category: | [[Category:Featured in BAMBED]] | ||