Monoacylglycerol lipase explained

acylglycerol lipase
Ec Number:3.1.1.23
Cas Number:9040-75-9
Go Code:0047372
Caption:Reaction catalyzed by MGLL, in which a free fatty acid (FFA) is released from a monoacylglycerol (MAG)
monoglyceride lipase
Hgncid:17038
Symbol:MGLL
Entrezgene:11343
Omim:609699
Refseq:NM_007283
Uniprot:Q99685
Ecnumber:3.1.1.23
Chromosome:3
Arm:p
Band:13
Locussupplementarydata:-q13.33

Monoacylglycerol lipase (EC 3.1.1.23; systematic name glycerol-ester acylhydrolase, also known as MAG lipase, acylglycerol lipase, MAGL, MGL or MGLL) is an enzyme 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.[4]

Function

Monoacylglycerol lipase catalyzes a reaction that uses water molecules to break the glycerol monoesters of long-chain fatty acids:

hydrolyses glycerol monoesters of long-chain fatty acids

It 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, for instance URB-602, URB-754, and JZL-184, produce cannabinoid-like behavioral effects in mice.

Further examples include:[12]

As well as the following compounds which are under pharmaceutical development:

See also

References

External links

Notes and References

  1. Wall EM, Cao J, Chen N, Buller RM, Upton C . A novel poxvirus gene and its human homolog are similar to an E. coli lysophospholipase . Virus Research . 52 . 2 . 157–67 . December 1997 . 9495531 . 10.1016/S0168-1702(97)00122-6 .
  2. Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C . 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 . October 1997 . 9341166 . 10.1074/jbc.272.43.27218 . free .
  3. Web site: Entrez Gene: monoglyceride lipase .
  4. Tornqvist H, Belfrage P . Purification and some properties of a monoacylglycerol-hydrolyzing enzyme of rat adipose tissue . The Journal of Biological Chemistry . 251 . 3 . 813–9 . February 1976 . 10.1016/S0021-9258(17)33857-7 . 1249056 . free .
  5. Karlsson M, Reue K, Xia YR, Lusis AJ, Langin D, Tornqvist H, Holm C . Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene . Gene . 272 . 1–2 . 11–8 . July 2001 . 11470505 . 10.1016/S0378-1119(01)00559-5 .
  6. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D . Brain monoglyceride lipase participating in endocannabinoid inactivation . Proceedings of the National Academy of Sciences of the United States of America . 99 . 16 . 10819–24 . August 2002 . 12136125 . 125056 . 10.1073/pnas.152334899 . 2002PNAS...9910819D . free .
  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 . Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus . Nature Neuroscience . 8 . 9 . 1139–41 . September 2005 . 16116451 . 10.1038/nn1521 . 52810445 . free .
  8. Book: Cannabinoid Receptors—Advances in Research and Application: 2012 Edition: ScholarlyBrief. 26 December 2012. ScholarlyEditions. 978-1-4816-0672-1. 68–.
  9. Blankman JL, Simon GM, Cravatt BF . A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol . Chemistry & Biology . 14 . 12 . 1347–56 . December 2007 . 18096503 . 2692834 . 10.1016/j.chembiol.2007.11.006 .
  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 . Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects . Nature Chemical Biology . 5 . 1 . 37–44 . January 2009 . 19029917 . 2605181 . 10.1038/nchembio.129 .
  11. Savinainen JR, Saario SM, Laitinen JT . The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors . Acta Physiologica . 204 . 2 . 267–76 . February 2012 . 21418147 . 3320662 . 10.1111/j.1748-1716.2011.02280.x .
  12. Kanwal H, Sangineto M, Ciarnelli M, Castaldo P, Villani R, Romano AD, Serviddio G, Cassano T . Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer's Disease . Int J Mol Sci . 25 . 7 . April 2024 . 4050 . 38612861 . 11012768 . 10.3390/ijms25074050 . free .
  13. Web site: CC 97489 . AdisInsight . 28 February 2024 . 9 August 2024.
  14. Web site: Elcubragistat . AdisInsight . 28 July 2024 . 9 August 2024.
  15. Web site: PF 6818883 . AdisInsight . 28 December 2019 . 9 August 2024.
  16. Web site: RG 6182 . AdisInsight . 26 February 2024 . 9 August 2024.
  17. Web site: Monoacylglycerol lipase inhibitor (Small molecule MGLLi) . AdisInsight . 22 August 2022 . 9 August 2024.

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