Sandbox Reserved 919: Difference between revisions

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<StructureSection load='3PE6' size='300' frame='true' align='right' caption= 'Structure' scene='57/573133/Generic_monomer/3'>
<StructureSection load='3PE6' size='300' frame='true' align='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/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 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/3'>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/4'>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].
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].

Revision as of 04:24, 24 April 2014

This Sandbox is Reserved from Jan 06, 2014, through Aug 22, 2014 for use by the Biochemistry II class at the Butler University at Indianapolis, IN USA taught by R. Jeremy Johnson. This reservation includes Sandbox Reserved 911 through Sandbox Reserved 922.
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Monoglyceride LipaseMonoglyceride Lipase

File:MGLProt.jpg
Figure 1: Monomer of MGL created in PYMOL (PDB:3PE6), colored by secondary structure.

IntroductionIntroduction

Monoglyceride Lipase (MGL, MAGL, MGLL) is a 33 kDa protein [1] found mostly in the cell membrane . MGL is a serine hydrolase enzyme that contains an α/β hydrolase fold. MGL plays a key role in the hydrolysis of 2-arachidonoylglycerol (2-AG), an endocannabinoid produced by the the central nervous system.[1][2][3][4] The hydrolase fold, along with a characteristic amphipathic occluded tunnel, allows 2-AG to selectively bind to the active site of MGL and be degraded into 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. [1] [2] 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. [5] [6]

StructureStructure

3D Structure

The first complete crystal structure of MGL was determined in 2009 in its apo form. [2] MGL is a part of the α-β hydrolase family of enzymes.[1][2][3] This category of proteins contains an beta sheet, specifically containing seven parallel and one antiparallel constituent strand, by alpha-helices. [2]

MGL has a characteristic lid domain comprised of two large loops that surround .[2] This region of the enzyme is the membrane-interacting moiety of the protein, which is consistent with its amphipathic nature and outward-facing (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.[2] 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 crystallographic studies. [2] Currently, there is no consensus regarding the quaternary arrangement of MGL. Some studies show that MGL is primarily found as a monomer, [2] [3] whereas other studies have found it to be a physiologically active . [1] One compelling piece of evidence for the dimeric quartenary structure is the presence of a pair of beta strands between the two molecules of MGL in 3JW8.

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 monoacylglycerols, the tunnel is largely amphipathic. Hydrophobic residues dominate the tunnel with the exception of the terminal occluded region, which houses the catalytic triad. In its apo form, the catalytic region is not solvent-exposed, unlike the wide opening of the tunnel. [1][2] 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. [1][2][3]

Catalytic Triad

MGL’s serine hydrolase chemistry is executed by a (Ser132-His279-Asp249) and seems to utilize the same mechanism as the much-studied chymotrypsin. In this mechanism, an activated serine nucleophile cleaves the ester bond of the substrate.[1][2][3] The subsequent tetrahedral intermediate is stabilized by the , formed by the main-chain nitrogens of Ala61 and Met (or Se-Met) 133.[2]


Biological/Medical Relevance

2-AG Metabolism

2-AG activates the same cannabinoid receptors (CB1 and CB2) for both anandamide and the main psychoactive compound found in Cannabis sativa, Δ9-Tetrahydrocannabinol (THC), via retrograde signaling. [2] 2-AG is the most abundant endocannabinoid found in the brain, possessing analgesic, anti-inflammatory, immunomodulating, neuroprotective, and hypotensive effects.[1][5]

Approximately 85% of the 2-AG in the rat brain is metabolized by MGL, while other lipases such as fatty acid amide hydrolase (FAAH) process the remainder of the metabolite.[4] 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. [1][2][3] 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. [1][3]

MGL Inhibitors

Three general MGL inhibitor classes have been observed: noncompetitive, partially irreversible inhibitors such as URB602; irreversible serine-reactive inhibitors such as JZL184 and ; and cysteine-reactive inhibitors such as N-arachidonoylmaleimide (NAM). [2] 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. [1]


Structure

Drag the structure with the mouse to rotate

Cancer ResearchCancer Research

MGL is also a target for continuing cancer research, with the potential to help distinguish the role of fatty acids in 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 carcinogenesis. [6]

MGL exerts a twofold influence on cancer growth; endocannabinoids such as 2-AG have been shown to have anti-tumorigenic properties [1] [5] 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. Subsequently, the creation of effective MGL inhibitors may help to treat highly aggressive cancers in addition to their proposed use as analgesics. [6]

Recent evidence, however, has found 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 PI3K/Akt signaling and tumor growth pathway. MGL serves as a negative effector in this role: as concentrations of MGL decrease, Akt phosphorylation increase. [6]

MGL’s role in different body tissues is an ongoing area of research in order to elucidate its complex role in cancer pathology. MGL’s effect on exogenous cannabinoid medications given to cancer patients as a palliative medication is a potential and promising lead. [5]


ReferencesReferences

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Labar G, Bauvois C, Borel F, Ferrer JL, Wouters J, Lambert DM. Crystal structure of the human monoacylglycerol lipase, a key actor in endocannabinoid signaling. Chembiochem. 2010 Jan 25;11(2):218-27. PMID:19957260 doi:10.1002/cbic.200900621
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 Bertrand T, Auge F, Houtmann J, Rak A, Vallee F, Mikol V, Berne PF, Michot N, Cheuret D, Hoornaert C, Mathieu M. Structural basis for human monoglyceride lipase inhibition. J Mol Biol. 2010 Feb 26;396(3):663-73. Epub 2009 Dec 3. PMID:19962385 doi:10.1016/j.jmb.2009.11.060
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Schalk-Hihi C, Schubert C, Alexander R, Bayoumy S, Clemente JC, Deckman I, Desjarlais RL, Dzordzorme KC, Flores CM, Grasberger B, Kranz JK, Lewandowski F, Liu L, Ma H, Maguire D, Macielag MJ, McDonnell ME, Haarlander TM, Miller R, Milligan C, Reynolds C, Kuo LC. Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A resolution. Protein Sci. 2011 Feb 3. doi: 10.1002/pro.596. PMID:21308848 doi:10.1002/pro.596
  4. ↑ 4.0 4.1 Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 2007 Dec;14(12):1347-56. PMID:18096503 doi:http://dx.doi.org/10.1016/j.chembiol.2007.11.006
  5. ↑ 5.0 5.1 5.2 5.3 Nomura DK, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, Hoover HH, Cravatt BF. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol. 2011 Jul 29;18(7):846-56. doi: 10.1016/j.chembiol.2011.05.009. PMID:21802006 doi:http://dx.doi.org/10.1016/j.chembiol.2011.05.009
  6. ↑ 6.0 6.1 6.2 6.3 Sun H, Jiang L, Luo X, Jin W, He Q, An J, Lui K, Shi J, Rong R, Su W, Lucchesi C, Liu Y, Sheikh MS, Huang Y. Potential tumor-suppressive role of monoglyceride lipase in human colorectal cancer. Oncogene. 2013 Jan 10;32(2):234-41. doi: 10.1038/onc.2012.34. Epub 2012 Feb 20. PMID:22349814 doi:http://dx.doi.org/10.1038/onc.2012.34

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA, Nathan Alexander Holt, Steven Han, Gregory Zemtsov, R. Jeremy Johnson
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