Monoacylglycerol lipase: Difference between revisions

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{{infobox protein
{{infobox protein
|Name=monoglyceride lipase
|Name=monoglyceride lipase
|caption=
|caption= Reaction catalyzed by MGLL, in which a free fatty acid (FFA) is released from a monoacylglycerol (MAG)
|image=
|image= Image:Mgll_activity.png
|width=
|width=
|HGNCid=17038
|HGNCid=17038
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|LocusSupplementaryData=-q13.33
|LocusSupplementaryData=-q13.33
}}
}}
'''Monoacylglycerol lipase''', also known as MAG lipase, '''MAGL''',''' MGL''' or '''MGLL''' is a [[protein]] that, in humans, is encoded by the ''MGLL'' [[gene]].<ref name="pmid9495531">{{cite journal | vauthors = Wall EM, Cao J, Chen N, Buller RM, Upton C | title = A novel poxvirus gene and its human homolog are similar to an E. coli lysophospholipase | journal = Virus Research | volume = 52 | issue = 2 | pages = 157–67 | date = Dec 1997 | pmid = 9495531 | doi = 10.1016/S0168-1702(97)00122-6 }}</ref><ref name="pmid9341166">{{cite journal | vauthors = Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C | title = cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases | journal = The Journal of Biological Chemistry | volume = 272 | issue = 43 | pages = 27218–23 | date = Oct 1997 | pmid = 9341166 | doi = 10.1074/jbc.272.43.27218 }}</ref><ref>{{cite web | title = Entrez Gene: monoglyceride lipase | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11343 | accessdate = }}</ref> MAGL is a 33-kDa, membrane-associated member of the [[serine hydrolase]] superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The [[catalytic triad]] has been identified as Ser122, His269, and Asp239.<ref name="pmid9341166" /><ref>{{cite journal | vauthors = Tornqvist H, Belfrage P | title = Purification and some properties of a monoacylglycerol-hydrolyzing enzyme of rat adipose tissue | journal = The Journal of Biological Chemistry | volume = 251 | issue = 3 | pages = 813–9 | date = Feb 1976 | pmid = 1249056 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1249056 }}</ref>
'''Monoacylglycerol lipase''', also known as MAG lipase, '''MAGL''',''' MGL''' or '''MGLL''' is a [[protein]] that, in humans, is encoded by the ''MGLL'' [[gene]].<ref name="pmid9495531">{{cite journal | vauthors = Wall EM, Cao J, Chen N, Buller RM, Upton C | title = A novel poxvirus gene and its human homolog are similar to an E. coli lysophospholipase | journal = Virus Research | volume = 52 | issue = 2 | pages = 157–67 | date = Dec 1997 | pmid = 9495531 | doi = 10.1016/S0168-1702(97)00122-6 }}</ref><ref name="pmid9341166">{{cite journal | vauthors = Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C | title = cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases | journal = The Journal of Biological Chemistry | volume = 272 | issue = 43 | pages = 27218–23 | date = Oct 1997 | pmid = 9341166 | doi = 10.1074/jbc.272.43.27218 }}</ref><ref>{{cite web | title = Entrez Gene: monoglyceride lipase | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11343 | accessdate = }}</ref> MAGL is a 33-kDa, membrane-associated member of the [[serine hydrolase]] superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The [[catalytic triad]] has been identified as Ser122, His269, and Asp239.<ref name="pmid9341166" /><ref>{{cite journal | vauthors = Tornqvist H, Belfrage P | title = Purification and some properties of a monoacylglycerol-hydrolyzing enzyme of rat adipose tissue | journal = The Journal of Biological Chemistry | volume = 251 | issue = 3 | pages = 813–9 | date = Feb 1976 | pmid = 1249056 }}</ref>


== Function ==
== Function ==


[[Monoacylglycerol]] [[lipase]] functions together with [[hormone-sensitive lipase]] (LIPE) to hydrolyze intracellular triglyceride stores in adipocytes and other cells to fatty acids and glycerol. MGLL may also complement [[lipoprotein lipase]] (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.<ref name="pmid11470505">{{cite journal | vauthors = Karlsson M, Reue K, Xia YR, Lusis AJ, Langin D, Tornqvist H, Holm C | title = Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene | journal = Gene | volume = 272 | issue = 1–2 | pages = 11–8 | date = Jul 2001 | pmid = 11470505 | doi = 10.1016/S0378-1119(01)00559-5 }}</ref>
[[Monoacylglycerol]] [[lipase]] functions together with [[hormone-sensitive lipase]] (LIPE) to hydrolyze intracellular triglyceride stores in adipocytes and other cells to fatty acids and glycerol. MGLL may also complement [[lipoprotein lipase]] (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.<ref name="pmid11470505">{{cite journal | vauthors = Karlsson M, Reue K, Xia YR, Lusis AJ, Langin D, Tornqvist H, Holm C | title = Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene | journal = Gene | volume = 272 | issue = 1-2 | pages = 11–8 | date = July 2001 | pmid = 11470505 | doi = 10.1016/S0378-1119(01)00559-5 }}</ref>


Monoacylglycerol lipase is a key enzyme in the hydrolysis of the [[endocannabinoid]] [[2-arachidonoylglycerol]] (2-AG).<ref name="pmid12136125">{{cite journal | vauthors = Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D | title = Brain monoglyceride lipase participating in endocannabinoid inactivation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 16 | pages = 10819–24 | date = Aug 2002 | pmid = 12136125 | pmc = 125056 | doi = 10.1073/pnas.152334899 }}</ref><ref name="pmid16116451">{{cite journal | vauthors = Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D | title = Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus | journal = Nature Neuroscience | volume = 8 | issue = 9 | pages = 1139–41 | date = Sep 2005 | pmid = 16116451 | doi = 10.1038/nn1521 }}</ref>  It converts [[monoacylglycerol]]s to the free [[fatty acid]] and [[glycerol]]. The contribution of MAGL to total brain 2-AG hydrolysis activity has been estimated to be ~85% ([[ABHD6]] and [[ABHD12]] are responsible for ~4% and ~9%, respectively, of the remainder),<ref name="ScholarlyEditions2012">{{cite book|title=Cannabinoid Receptors—Advances in Research and Application: 2012 Edition: ScholarlyBrief|url=https://books.google.com/books?id=QZqtIuUdJnQC&pg=PA68|date=26 December 2012|publisher=ScholarlyEditions|isbn=978-1-4816-0672-1|pages=68–}}</ref><ref name="pmid18096503">{{cite journal | vauthors = Blankman JL, Simon GM, Cravatt BF | title = A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol | journal = Chemistry & Biology | volume = 14 | issue = 12 | pages = 1347–56 | date = Dec 2007 | pmid = 18096503 | pmc = 2692834 | doi = 10.1016/j.chembiol.2007.11.006 }}</ref> and this ''in vitro'' estimate has been confirmed ''in vivo'' by the selective MAGL inhibitor [[JZL184]].<ref name="pmid19029917">{{cite journal | vauthors = Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF | title = Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects | journal = Nature Chemical Biology | volume = 5 | issue = 1 | pages = 37–44 | date = Jan 2009 | pmid = 19029917 | pmc = 2605181 | doi = 10.1038/nchembio.129 }}</ref> Chronic inactivation of MAGL results in massive (>10-fold) elevations of brain 2-AG in mice, along with marked compensatory [[downregulation]] of CB<sub>1</sub> receptors in selective brain areas.<ref name="SavinainenSaario2012">{{cite journal | vauthors = Savinainen JR, Saario SM, Laitinen JT | title = The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors | journal = Acta Physiologica | volume = 204 | issue = 2 | pages = 267–76 | date = Feb 2012 | pmid = 21418147 | doi = 10.1111/j.1748-1716.2011.02280.x | pmc=3320662}}</ref>
Monoacylglycerol lipase is a key enzyme in the hydrolysis of the [[endocannabinoid]] [[2-arachidonoylglycerol]] (2-AG).<ref name="pmid12136125">{{cite journal | vauthors = Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D | title = Brain monoglyceride lipase participating in endocannabinoid inactivation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 16 | pages = 10819–24 | date = August 2002 | pmid = 12136125 | pmc = 125056 | doi = 10.1073/pnas.152334899 }}</ref><ref name="pmid16116451">{{cite journal | vauthors = Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D | title = Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus | journal = Nature Neuroscience | volume = 8 | issue = 9 | pages = 1139–41 | date = September 2005 | pmid = 16116451 | doi = 10.1038/nn1521 }}</ref>  It converts [[monoacylglycerol]]s to the free [[fatty acid]] and [[glycerol]]. The contribution of MAGL to total brain 2-AG hydrolysis activity has been estimated to be ~85% ([[ABHD6]] and [[ABHD12]] are responsible for ~4% and ~9%, respectively, of the remainder),<ref name="ScholarlyEditions2012">{{cite book|title=Cannabinoid Receptors—Advances in Research and Application: 2012 Edition: ScholarlyBrief|url=https://books.google.com/books?id=QZqtIuUdJnQC&pg=PA68|date=26 December 2012|publisher=ScholarlyEditions|isbn=978-1-4816-0672-1|pages=68–}}</ref><ref name="pmid18096503">{{cite journal | vauthors = Blankman JL, Simon GM, Cravatt BF | title = A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol | journal = Chemistry & Biology | volume = 14 | issue = 12 | pages = 1347–56 | date = December 2007 | pmid = 18096503 | pmc = 2692834 | doi = 10.1016/j.chembiol.2007.11.006 }}</ref> and this ''in vitro'' estimate has been confirmed ''in vivo'' by the selective MAGL inhibitor [[JZL184]].<ref name="pmid19029917">{{cite journal | vauthors = Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF | title = Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects | journal = Nature Chemical Biology | volume = 5 | issue = 1 | pages = 37–44 | date = January 2009 | pmid = 19029917 | pmc = 2605181 | doi = 10.1038/nchembio.129 }}</ref> Chronic inactivation of MAGL results in massive (>10-fold) elevations of brain 2-AG in mice, along with marked compensatory [[downregulation]] of CB<sub>1</sub> receptors in selective brain areas.<ref name="SavinainenSaario2012">{{cite journal | vauthors = Savinainen JR, Saario SM, Laitinen JT | title = The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors | journal = Acta Physiologica | volume = 204 | issue = 2 | pages = 267–76 | date = February 2012 | pmid = 21418147 | pmc = 3320662 | doi = 10.1111/j.1748-1716.2011.02280.x }}</ref>


==Inhibitors and assay==
== Inhibitors ==
The enzyme was reported to be inhibited by [[URB754]]; however this inhibitor has subsequently been shown to be inactive and its reported activity due to contamination.<ref name="pmid16931330">{{cite journal | vauthors = Saario SM, Palomäki V, Lehtonen M, Nevalainen T, Järvinen T, Laitinen JT | title = URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain | journal = Chemistry & Biology | volume = 13 | issue = 8 | pages = 811–4 | date = Aug 2006 | pmid = 16931330 | doi = 10.1016/j.chembiol.2006.07.008 }}</ref> While the compound ''N''-arachidonoyl maleimide (NAM) inhibits MAGL,<ref name="pmid18682568">{{cite journal | vauthors = Burston JJ, Sim-Selley LJ, Harloe JP, Mahadevan A, Razdan RK, Selley DE, Wiley JL | title = N-arachidonyl maleimide potentiates the pharmacological and biochemical effects of the endocannabinoid 2-arachidonylglycerol through inhibition of monoacylglycerol lipase | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 546–53 | date = Nov 2008 | pmid = 18682568 | pmc = 2605346 | doi = 10.1124/jpet.108.141382 }}</ref> NAM is not selective due to its chemically reactive [[maleimide]] [[functional group]], which can also react with other [[thiol]]-containing [[small molecule]]s and [[protein]]s (e.g., [[glutathione]]).
MAGL [[enzyme inhibitor]]s ([[URB602]], [[URB754]], [[JZL184]]) produce [[cannabinoid]] behavioral effects in mice.<ref>{{citation | author=JZ Long et al. | title=Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects | journal=[[Nature Chemical Biology]] | volume=5 | issue=1 | year=2009 | pages=37-44 | pmid=19029917}}</ref>


[[JZL184]] is the first efficacious and selective inhibitor of MAGL that can elevate brain 2-AG levels in vivo.<ref name="pmid19029917" /> JZL184 has >300-fold selectivity for MAGL over other brain [[serine hydrolase]]s, including [[FAAH]].
Further examples include:
 
#[[KML-29]]
MAGL activity is commonly detected by measuring free fatty acid release from a monoacylglycerol substrate using a [[liquid chromatography]] [[mass spectrometry]] system or the radiolabelled substrate 2-oleoyl-[<sup>3</sup>H]-glycerol.
#[[JZL195]]
 
#[[JNJ-42165279]]
==Reaction==
#[[JW 642]]
[[Image:Mgll_activity.png|thumb|center|400px|Reaction catalyzed by MGLL, in which a free fatty acid (FFA) is released from a monoacylglycerol (MAG).]]


== See also ==
== See also ==
Line 40: Line 39:
* [[Endocannabinoid reuptake inhibitor]]
* [[Endocannabinoid reuptake inhibitor]]
* [[Triacylglycerol lipase]]
* [[Triacylglycerol lipase]]
* [[Fatty acid amide hydrolase]]


== References ==
== References ==
{{Reflist|33em}}
{{Reflist}}


== External links ==
== External links ==

Latest revision as of 23:13, 20 December 2018

monoglyceride lipase
File:Mgll activity.png
Reaction catalyzed by MGLL, in which a free fatty acid (FFA) is released from a monoacylglycerol (MAG)
Identifiers
SymbolMGLL
Entrez11343
HUGO17038
OMIM609699
RefSeqNM_007283
UniProtQ99685
Other data
EC number3.1.1.23
LocusChr. 3 p13-q13.33

Monoacylglycerol lipase, also known as MAG lipase, MAGL, MGL or MGLL is a protein that, in humans, is encoded by the MGLL gene.[1][2][3] MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.[2][4]

Function

Monoacylglycerol lipase functions together with hormone-sensitive lipase (LIPE) to hydrolyze intracellular triglyceride stores in adipocytes and other cells to fatty acids and glycerol. MGLL may also complement lipoprotein lipase (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.[5]

Monoacylglycerol lipase is a key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG).[6][7] It converts monoacylglycerols to the free fatty acid and glycerol. The contribution of MAGL to total brain 2-AG hydrolysis activity has been estimated to be ~85% (ABHD6 and ABHD12 are responsible for ~4% and ~9%, respectively, of the remainder),[8][9] and this in vitro estimate has been confirmed in vivo by the selective MAGL inhibitor JZL184.[10] Chronic inactivation of MAGL results in massive (>10-fold) elevations of brain 2-AG in mice, along with marked compensatory downregulation of CB1 receptors in selective brain areas.[11]

Inhibitors

MAGL enzyme inhibitors (URB602, URB754, JZL184) produce cannabinoid behavioral effects in mice.[12]

Further examples include:

  1. KML-29
  2. JZL195
  3. JNJ-42165279
  4. JW 642

See also

References

  1. ↑ Wall EM, Cao J, Chen N, Buller RM, Upton C (Dec 1997). "A novel poxvirus gene and its human homolog are similar to an E. coli lysophospholipase". Virus Research. 52 (2): 157–67. doi:10.1016/S0168-1702(97)00122-6. PMID 9495531.
  2. ↑ 2.0 2.1 Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C (Oct 1997). "cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases". The Journal of Biological Chemistry. 272 (43): 27218–23. doi:10.1074/jbc.272.43.27218. PMID 9341166.
  3. ↑ "Entrez Gene: monoglyceride lipase".
  4. ↑ Tornqvist H, Belfrage P (Feb 1976). "Purification and some properties of a monoacylglycerol-hydrolyzing enzyme of rat adipose tissue". The Journal of Biological Chemistry. 251 (3): 813–9. PMID 1249056.
  5. ↑ Karlsson M, Reue K, Xia YR, Lusis AJ, Langin D, Tornqvist H, Holm C (July 2001). "Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene". Gene. 272 (1–2): 11–8. doi:10.1016/S0378-1119(01)00559-5. PMID 11470505.
  6. ↑ Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D (August 2002). "Brain monoglyceride lipase participating in endocannabinoid inactivation". Proceedings of the National Academy of Sciences of the United States of America. 99 (16): 10819–24. doi:10.1073/pnas.152334899. PMC 125056. PMID 12136125.
  7. ↑ Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D (September 2005). "Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus". Nature Neuroscience. 8 (9): 1139–41. doi:10.1038/nn1521. PMID 16116451.
  8. ↑ Cannabinoid Receptors—Advances in Research and Application: 2012 Edition: ScholarlyBrief. ScholarlyEditions. 26 December 2012. pp. 68–. ISBN 978-1-4816-0672-1.
  9. ↑ Blankman JL, Simon GM, Cravatt BF (December 2007). "A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol". Chemistry & Biology. 14 (12): 1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC 2692834. PMID 18096503.
  10. ↑ Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF (January 2009). "Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects". Nature Chemical Biology. 5 (1): 37–44. doi:10.1038/nchembio.129. PMC 2605181. PMID 19029917.
  11. ↑ Savinainen JR, Saario SM, Laitinen JT (February 2012). "The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors". Acta Physiologica. 204 (2): 267–76. doi:10.1111/j.1748-1716.2011.02280.x. PMC 3320662. PMID 21418147.
  12. ↑ JZ Long; et al. (2009), "Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects", Nature Chemical Biology, 5 (1): 37–44, PMID 19029917

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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