Monoacylglycerol lipase, also known as MAG lipase, MAGL, MGL or MGLL is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that, in humans, is encoded by the MGLL gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

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

Serine hydrolase

The serine hydrolase superfamily is one of the largest known enzyme families comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A characteristic defining feature of this superfamily is the presence of an active site nucleophilic serine that is used for the hydrolysis of...

 superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.

Function

Monoacylglycerol lipase

Lipase

A lipase is an enzyme that catalyzes the formation or cleavage of fats . Lipases are a subclass of the esterases.Lipases perform essential roles in the digestion, transport and processing of dietary lipids in most, if not all, living organisms...

 functions together with hormone-sensitive lipase

Hormone-sensitive lipase

Hormone-sensitive lipase also previously known as cholesteryl ester hydrolase is an enzyme that, in humans, is encoded by the LIPE gene....

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

Lipoprotein lipase

Lipoprotein lipase is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins , into two free...

 (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-Arachidonoylglycerol

2-Arachidonoylglycerol is an endocannabinoid, an endogenous agonist of the CB1 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been...

. It converts monoacylglycerols to the free fatty acid

Fatty acid

In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...

 and glycerol

Glycerol

Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...

. The contribution of MAGL to total brain 2-AG hydrolysis activity has been estimated to be ~85%, and this in vitro estimate has been confirmed in vivo by the selective MAGL inhibitor JZL184

JZL184

JZL184 is an irreversible inhibitor for monoacylglycerol lipase , the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol...

.

Inhibitors and assay

The enzyme was reported to be inhibited by URB754

URB754

URB754 was originally reported to be a potent, noncompetitive inhibitor of monoacylglycerol lipase. However, recent studies have shown that URB754 failed to inhibit recombinant MGL, and brain FAAH activity was also resistant to URB754. Some controversy in the field remains regarding the use of...

; however this inhibitor has subsequently been shown to be inactive and its reported activity due to contamination. While the compound N-arachidonoyl maleimide (NAM) inhibits MAGL, NAM is not selective due to its chemically reactive maleimide

Maleimide

Maleimide is the chemical compound with the formula H2C22NH . This unsaturated imide is an important building block in organic synthesis. The name is a contraction of maleic acid and imide, the -CNHC- functional group...

 functional group

Functional group

In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...

, which can also react with other thiol

Thiol

In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...

-containing small molecule

Small molecule

In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...

s and protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s (e.g., glutathione

Glutathione

Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

).

JZL184

JZL184

JZL184 is an irreversible inhibitor for monoacylglycerol lipase , the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol...

 is the first efficacious and selective inhibitor of MAGL that can elevate brain 2-AG levels in vivo. JZL184 has >300-fold selectivity for MAGL over other brain serine hydrolase

Serine hydrolase

The serine hydrolase superfamily is one of the largest known enzyme families comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A characteristic defining feature of this superfamily is the presence of an active site nucleophilic serine that is used for the hydrolysis of...

s, including FAAH

FAAH

Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. It was first shown to breakdown anandamide in 1993 . In humans, it is encoded by the gene FAAH.-Function:...

.

MAGL activity is commonly detected by measuring free fatty acid release from a monoacylglycerol substrate using a liquid chromatography mass spectrometry

Mass spectrometry

Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...

system or the radiolabelled substrate 2-oleoyl-[³H]-glycerol.

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