Monoacylglycerol lipase

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.

Monoacylglycerol lipase is a key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). 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), and this in vitro estimate has been confirmed in vivo by the selective MAGL inhibitor JZL184. 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.

Inhibitors

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

Further examples include:

• KML-29
• JZL-195 – dual MAGL and FAAH inhibitor
• JW-642

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

• CC-97489 – dual MAGL and FAAH inhibitor
• Elcubragistat (ABX-1431; Lu AG06466)
• PF-06818883
• RG-6182
• Small molecule MGLLi

References

References

1. (December 1997). "A novel poxvirus gene and its human homolog are similar to an ''E. coli'' lysophospholipase". Virus Research.
2. (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.
3. "Entrez Gene: monoglyceride lipase".
4. (February 1976). "Purification and some properties of a monoacylglycerol-hydrolyzing enzyme of rat adipose tissue". The Journal of Biological Chemistry.
5. (July 2001). "Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene". Gene.
6. (August 2002). "Brain monoglyceride lipase participating in endocannabinoid inactivation". Proceedings of the National Academy of Sciences of the United States of America.
7. (September 2005). "Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus". Nature Neuroscience.
8. (26 December 2012). "Cannabinoid Receptors—Advances in Research and Application: 2012 Edition: ScholarlyBrief". ScholarlyEditions.
9. (December 2007). "A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol". Chemistry & Biology.
10. (January 2009). "Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects". Nature Chemical Biology.
11. (February 2012). "The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors". Acta Physiologica.
12. (April 2024). "Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer's Disease". Int J Mol Sci.
13. (28 February 2024). "CC 97489".
14. (28 July 2024). "Elcubragistat".
15. (28 December 2019). "PF 6818883".
16. (26 February 2024). "RG 6182".
17. (22 August 2022). "Monoacylglycerol lipase inhibitor (Small molecule MGLLi)".