Monoacylglycerol lipase

Monoacylglycerol lipase, 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.[2][4]

Human monoacylglycerol lipase
acylglycerol lipase
Reaction catalyzed by MGLL, in which a free fatty acid (FFA) is released from a monoacylglycerol (MAG)
Identifiers
EC number3.1.1.23
CAS number9040-75-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
monoglyceride lipase
Identifiers
SymbolMGLL
NCBI gene11343
HGNC17038
OMIM609699
RefSeqNM_007283
UniProtQ99685
Other data
EC number3.1.1.23
LocusChr. 3 p13-q13.33

Function

Monoacylglycerol lipase catalyzes a chemical reaction that uses water molecules to break the 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 (URB602, URB754, JZL184) produce cannabinoid behavioral effects in mice.[10]

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 (December 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. Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C (October 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 (February 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. S2CID 52810445.
  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.
  • Mentlein R, Heiland S, Heymann E (1980). "Simultaneous purification and comparative characterization of six serine hydrolases from rat liver microsomes". Arch. Biochem. Biophys. 200 (2): 547–59. doi:10.1016/0003-9861(80)90386-0. PMID 6776896.
  • Pope JL, McPherson JC, Tidwell HC (1966). "A study of a monoglyceride-hydrolyzing enzyme of intestinal mucosa". J. Biol. Chem. 241 (10): 2306–10. PMID 5916497.

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