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 An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that, in humans, is encoded by the ''MGLL''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. MAGL is a 33-kDa, membrane-associated member of the

serine hydrolase Serine hydrolases are one of the largest known enzyme classes comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A defining characteristic of these enzymes is the presence of a particular serine at the active site, whic ...

superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The

catalytic triad A catalytic triad is a set of three coordinated amino acid residues that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, aminoac ...

has been identified as Ser122, His269, and Asp239. Monoglyceride lipase

Function

Monoacylglycerol Monoglycerides (also: acylglycerols or monoacylglycerols) are a class of glycerides which are composed of a molecule of glycerol linked to a fatty acid via an ester bond. As glycerol contains both primary and secondary alcohol groups two differe ...

lipase In biochemistry, lipase ( ) refers to a class of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; howe ...

catalyzes Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

a reaction that uses

water Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...

molecules to break the

glycerol Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...

monoesters of long-chain

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

s: : hydrolyses glycerol monoesters of long-chain fatty acids It functions together with

hormone-sensitive lipase Hormone-sensitive lipase (, HSL), also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the ''LIPE'' gene, and catalyzes the following reaction: ...

(LIPE) to hydrolyze intracellular triglyceride stores in adipocytes and other cells to fatty acids and glycerol. MGLL may also complement

lipoprotein lipase Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-solubl ...

(LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides. Monoacylglycerol lipase is a key enzyme in the hydrolysis of the

endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

2-arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is pres ...

(2-AG). It converts

monoacylglycerol Monoglycerides (also: acylglycerols or monoacylglycerols) are a class of glycerides which are composed of a molecule of glycerol linked to a fatty acid via an ester bond. As glycerol contains both primary and secondary alcohol groups two differe ...

s to the free

and

. The contribution of MAGL to total brain 2-AG hydrolysis activity has been estimated to be ~85% (

ABHD6 alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene. Function ABHD6 is a serine hydrolyzing enzyme that pos ...

and

ABHD12 alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ''ABHD12'' gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system. It is ...

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 In biochemistry, in the biology, biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell (biology), cell decreases the production and quantities of its cellular ...

of CB₁ receptors in selective brain areas.

Inhibitors

MAGL

enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its Enzyme activity, activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which Substrate (biochemistry), substrate molecules are converted ...

s, for instance URB-602, URB-754, and JZL-184, produce

cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

-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

* *

External links

* *
Monoglyceride lipase (MGLL) Human Protein Atlas
{{Portal bar, Biology, border=no EC 3.1.1 Enzymes of unknown structure

Function

Inhibitors

See also

References

External links