Monoacylglycerol Lipase

Supporting information

Monoacylglycerol lipase (MAGL, MGL) is a serine hydrolase that breaks down monoacylglycerols to glycerol and fatty acid. It is the primary enzyme responsible for the metabolism of 2-arachidonylglycerol (2-AG) in the brain, and is also involved in lipid signaling.

2-AG acts as an endocannabinoid - an endogenous agonist of GPR55, CB1 and CB2 receptors. MAGL hydrolyzes 2-AG, attenuating endocannabinoid signaling and also generating arachidonic acid, which can be used in the synthesis of pro-inflammatory eicosanoids such as PGE2. MAGL inhibitors can therefore exhibit both antinociceptive and anti-inflammatory effects.

2-AG is structurally similar to anandamide (AEA), but the latter is hydrolyzed by fatty acid amide hydrolase (FAAH). FAAH and MAGL co-localize with CB1 receptors in the hippocampus, cerebellum and amygdala, but are distributed in different areas of the synapse - FAAH is expressed postsynaptically, whilst MAGL is expressed in the presynaptic terminal. Both enzymes play an important role in retrograde endocannabinoid signaling, as 2-AG and AEA activate CB1 receptors expressed in the presynaptic terminal to inhibit neurotransmitter release. Hydrolysis of these endocannabinoids by FAAH and MAGL prevents persistent CB1 receptor activation and desensitization.

MAGL was initially discovered in the context of lipid signaling in adipocytes. The enzyme hormone sensitive lipase (HSL) hydrolyzes triacylglycerols to monoacylglycerols, which are in turn hydrolyzed by MAGL to release free fatty acids. This is the last step of hydrolysis in adipocytes, and provides fuel during periods of glucose deprivation. The free fatty acids released from monoacylglycerol hydrolysis may be used in the synthesis of prostaglandin E2 (PGE2) and lysophosphatidic acid (LPA), dysregulation of which has been linked to cancer. Recent research has shown that MAGL may control the generation of free fatty acids in cancer cells, enabling them to fuel tumor growth.

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
Monoacylglycerol Lipase Human MGLL NM_007283 Q99685
Mouse Mgll - O35678
Rat Mgll NM_138502 Q8R431

Literature for Monoacylglycerol Lipase

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