Any feedback?
Information on EC 3.1.1.23 - acylglycerol lipase and Organism(s) Homo sapiens
for references in articles please use BRENDA:EC3.1.1.23Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
3.1.1.23 acylglycerol lipaseSpecify your search results
Word Map
- 3.1.1.23
-
endocannabinoids
- cannabinoids
- 2-arachidonoylglycerol
- amide
- anandamide
- agonist
- diacylglycerol
- pain
-
arachidonic
- synaptic
- phospholipase
-
2-arachidonoyl
-
lipolytic
- adipose
- lipases
- prostaglandin
- triacylglycerols
-
anxiety
-
activity-based
-
presynaptic
-
rimonabant
-
nociceptive
-
analgesia
-
antinociceptive
- cannabis
-
cannabimimetic
-
neuropathic
- n-arachidonoylethanolamine
-
hormone-sensitive
- tetrahydrolipstatin
- 4-nitrophenyl
- n-acylethanolamine
- fluorophosphonate
- diagnostics
- hyperalgesia
- allodynia
-
endocannabinoid-mediated
- drug development
- nape-pld
-
depolarization-induced
- medicine
- chlorpyrifos
- synthesis
-
psychoactive
- delta9-tetrahydrocannabinol
-
catalepsy
- pharmacology
- lysophospholipase
- 2-monoacylglycerols
- marijuana
- oleoylethanolamide
-
post-heparin
-
anxiety-like
- palmitoylethanolamide
-
anxiolytic
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
monoacylglycerol lipase, monoglyceride lipase, mag lipase, rv0183, monoacylglycerol hydrolase, monoglyceride hydrolase, yju3p, mag hydrolase, acylglycerol lipase, atmagl8, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
fatty acyl monoester lipase
-
-
-
-
MAGL
MGL
monoacylglycerol hydrolase
-
-
-
-
monoacylglycerol lipase
monoglyceridase
-
-
-
-
monoglyceride hydrolase
-
-
-
-
monoglyceride lipase
monoglyceridyllipase
-
-
-
-
MGL
-
-
monoacylglycerol lipase
-
-
-
-
monoacylglycerol lipase
-
-
monoacylglycerol lipase
-
monoglyceride lipase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of carboxylic ester
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
glycerol-ester acylhydrolase
-
CAS REGISTRY NUMBER
COMMENTARY
9040-75-9
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
1,3-dihydroxypropan-2-yl 4-pyren-1-ylbutanoate + H2O
pyrenylbutanoic acid + glycerol
-
-
-
-
?
1-palmitoyl-2-lysophosphatidylcholine + H2O
palmitic acid + glycerophosphorylcholine
-
-
-
-
?
4-methylumbelliferyl butyrate + H2O
4-methylumbelliferol + butyrate
-
-
-
?
7-hydroxyresorufinyl arachidonate + H2O
7-hydroxyresorufin + arachidonate
a red fluorogenic substrate, 7-HRA, that is stable in 10% DMSO for at least 36 h at room temperature and for at least 6 months at 4°C, synthesis, overview
-
-
?
arachidonoyl-7-hydroxy-6-methoxy-4-methylcoumarin ester + H2O
arachidonic acid + 7-hydroxy-6-methoxy-4-methylcoumarin
1-arachidonoylglycerol + H2O
glycerol + arachidonic acid
best substrate
-
-
?
2-(15-deoxy-DELTA12,14-prostaglandin J2)-glycerol + H2O
?
highest preference
-
-
?
2-arachidonoylglycerol + H2O
arachidonic acid + glycerol
-
-
-
-
?
2-arachidonoylglycerol + H2O
arachidonic acid + glycerol
-
the enzyme is responsible for degradation of 2-arachidonoylglycerol in HeLa cells
-
-
?
2-arachidonoylglycerol + H2O
arachidonic acid + glycerol
MGL modulates endocannabinoid signaling in vivo by inactivating 2-arachidonoylglycerol (2-AG), the main endogenous agonist for central CB1 and peripheral CB2 cannabinoid receptors
-
-
?
2-arachidonoylglycerol + H2O
arachidonic acid + glycerol
2-arachidonoylglycerol is bound in the tetrahedral intermediate state to Ser122
-
-
?
2-arachidonoylglycerol + H2O
arachidonic acid + glycerol
the MGL binding site is a single hydrophobic channel, consisting of an L-shaped main channel with a sub-pocket at the turn. The catalytic S122 of MGL is positioned at the bottom of a single channel
-
-
?
2-arachidonoylglycerol + H2O
glycerol + arachidonic acid
-
-
-
-
?
4-nitrophenyl acetate + H2O
4-nitrophenol + acetate
-
-
-
?
7-hydroxycoumarinyl arachidonate + H2O
7-hydroxycoumarin + arachidonate
-
-
-
?
7-hydroxycoumarinyl arachidonate + H2O
7-hydroxycoumarin + arachidonate
fluorescence detection using a fluorogenic probe 1,3-dihydroxypropan-2-yl-4-pyren-1-ylbutanoate
-
-
?
arachidonoyl-7-hydroxy-6-methoxy-4-methylcoumarin ester + H2O
arachidonic acid + 7-hydroxy-6-methoxy-4-methylcoumarin
-
-
-
-
?
arachidonoyl-7-hydroxy-6-methoxy-4-methylcoumarin ester + H2O
arachidonic acid + 7-hydroxy-6-methoxy-4-methylcoumarin
-
-
-
?
additional information
?
-
-
developmental and nutritional regulation of the enzyme in the intestine, overview
-
-
?
additional information
?
-
-
key enzyme responsible for the termination of endocannabinoid signaling with a crucial role in 2-arachidonoylglycerol metabolism, MAGL is unable to mediate anandamide degradation, overview
-
-
?
additional information
?
-
direct NMR detection of a reversible equilibrium between active and inactive states of human MGL (hMGL) that is slow on the NMR time scale and can be modulated in a controlled manner by pH, temperature, and select point mutations
-
-
?
additional information
?
-
-
direct NMR detection of a reversible equilibrium between active and inactive states of human MGL (hMGL) that is slow on the NMR time scale and can be modulated in a controlled manner by pH, temperature, and select point mutations
-
-
?
additional information
?
-
human monoacylglycerol lipase (MAGL) displays catalytic activity on monoacyl glycerols with medium to long-chain lipophylic moieties such as stearoyl, palmitoyl, oleoyl, and especially arachidonoyl groups. MAGL also demonstrates preference for the hydrolysis of 2-acyl glycerols over their 1(3)-regioisomers. Measurement of MAGL-catalyzed hydrolysis of p-nitrophenyl alkyl esters by monitoring the liberation of p-nitrophenol. Fluorogenic enzyme assay method evaluation, overview
-
-
?
additional information
?
-
-
human monoacylglycerol lipase (MAGL) displays catalytic activity on monoacyl glycerols with medium to long-chain lipophylic moieties such as stearoyl, palmitoyl, oleoyl, and especially arachidonoyl groups. MAGL also demonstrates preference for the hydrolysis of 2-acyl glycerols over their 1(3)-regioisomers. Measurement of MAGL-catalyzed hydrolysis of p-nitrophenyl alkyl esters by monitoring the liberation of p-nitrophenol. Fluorogenic enzyme assay method evaluation, overview
-
-
?
additional information
?
-
usage of a substrate with linoleic acid at the sn-1 position for enzyme activity assays
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
1-arachidonoylglycerol + H2O
glycerol + arachidonic acid
best substrate
-
-
?
arachidonoyl-7-hydroxy-6-methoxy-4-methylcoumarin ester + H2O
arachidonic acid + 7-hydroxy-6-methoxy-4-methylcoumarin
-
-
-
?
2-arachidonoylglycerol + H2O
arachidonic acid + glycerol
-
the enzyme is responsible for degradation of 2-arachidonoylglycerol in HeLa cells
-
-
?
2-arachidonoylglycerol + H2O
arachidonic acid + glycerol
MGL modulates endocannabinoid signaling in vivo by inactivating 2-arachidonoylglycerol (2-AG), the main endogenous agonist for central CB1 and peripheral CB2 cannabinoid receptors
-
-
?
additional information
?
-
-
developmental and nutritional regulation of the enzyme in the intestine, overview
-
-
?
additional information
?
-
-
key enzyme responsible for the termination of endocannabinoid signaling with a crucial role in 2-arachidonoylglycerol metabolism, MAGL is unable to mediate anandamide degradation, overview
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(3R)-1-(3,4-dimethylphenyl)-5-oxo-N-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]pyrrolidine-3-carboxamide
51.85% residual activity at 0.1 mM
(3R)-N-(3,5-dimethylphenyl)-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-oxopyrrolidine-3-carboxamide
18.61% residual activity at 0.1 mM
(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one
-
16% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
(3S)-N-(1,3-benzodioxol-4-ylmethyl)-1-[4-[(2-chlorobenzyl)oxy]phenyl]-5-oxopyrrolidine-3-carboxamide
51.09% residual activity at 0.1 mM
1-(3-phenylpropanoyl)-(3R,4R)-3-[1(R)-(3-phenylpropanoyloxy)-ethyl]-4-(acetoxy)-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(3-phenylpropanoyl)-(3R,4R)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-4-(acetoxy)-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(3-phenylpropanoyl)-(3R,4R)-3-[1(R)-(biphenylacetyloxy)-ethyl]-4-(acetoxy)-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0; 66% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(3-phenylpropanoyl)-(3S)-3-[1(R)-(3-phenylpropanoyloxy)-ethyl]-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(3-phenylpropanoyl)-(3S)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(3-phenylpropanoyl)-(3S)-3-[1(R)-(5-phenylpentanoyloxy)-ethyl]-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(3-phenylpropanoyl)-(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one
-
31% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(4-phenylbutanoyl)-(3R,4R)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-4-(acetoxy)-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(4-phenylbutanoyl)-(3R,4R)-3-[1(R)-hydroxyethyl]-4-(acetoxy)-azetidin-2-one
-
61% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(4-phenylbutanoyl)-(3S)-3-[1(R)-(3-phenylpropanoyloxy)-ethyl]-azetidin-2-one
-
54% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(4-phenylbutanoyl)-(3S)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one
-
100% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(4-phenylbutanoyl)-(3S)-3-[1(R)-(5-phenylpentanoyloxy)-ethyl]-azetidin-2-one
-
59% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(5-phenylpentanoyl)-(3S)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one
-
39% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(5-phenylpentanoyl)-(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one
-
25% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(hexa-5-enoyl)-(3S)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one
-
85% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(hexa-5-enoyl)-(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one
-
67% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(pent-4-enoyl)-(3R,4R)-3-[1(R)-(pent-4-enoyloxy)-ethyl]-4-(acetoxy)-azetidin-2-one
-
99% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(pent-4-enoyl)-(3R,4R)-3-[1(R)-hydroxyethyl]-4-(acetoxy)-azetidin-2-one
-
16% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0; 8% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(pent-4-enoyl)-(3S)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one
-
89% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(pent-4-enoyl)-(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one
-
91% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(pent-4-enoyl)-(3S)-3-[1(R)-(hexa-5-enoyloxy)-ethyl]-azetidin-2-one
-
8% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(pent-4-enoyl)-(3S)-3-[1(R)-(pent-4-enoyloxy)-ethyl]-azetidin-2-one
-
99% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1-(pent-4-enoyl)-(3S)-3-[1(R)-hydroxyethyl]-azetidin-2-one
-
89% inhibition, with 0.1 mM of inhibitor, at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
1H-benzotriazol-1-yl[4-[(2E)-3-phenylprop-2-en-1-yl]piperazin-1-yl]methanone
-
2-(4-hydroxyphenyl)ethyl alpha-L-rhamnopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->6)]-2-O-acetyl-4-O-(4-coumaroyl)-beta-D-glucopyranoside
-
2-(4-hydroxyphenyl)ethyl alpha-L-rhamnopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->6)]-2-O-acetyl-4-O-beta-D-glucopyranoside
the inhibitor is selective for hMAGL over hLDH, modeling of the binding mode in the MAGL active site. The sugar moiety lies in the wide lipophilic cavity of the protein forming lipophilic interactions with L148, L213, L241, and V183, whereas the 4-hydroxyphenyl-ethyl ring lies into the small pocket of the binding site and forms lipophilic interactions with residues Y194 and V270. A high number of H-bonds stabilizes the binding disposition of the compound
2-(4-hydroxyphenyl)ethyl alpha-L-rhamnopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->6)]-beta-D-glucopyranoside
-
2-(7-methoxy-2-oxo-2H-chromen-3-yl)-N-(2-methoxyphenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide
-
3-[(4S)-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-2,5-dioxoimidazolidin-4-yl]-N-[(1R,2R)-2-methylcyclohexyl]propanamide
57.6% residual activity at 0.1 mM
4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]piperidine-1-carboxylate
-
JZL184
5-[(biphenyl-4-yl)methyl]-N,N-dimethyl-2H-tetrazole-2-carboxamide
AM6701, conforms to the L shape of the binding site, contacts with the binding site are similar to those seen with the 2-arachidonoylglycerol docking pose. The close contacts with A164 and K165 are lost as the subpocket is not occupied. Instead the biphenyl moiety, which extends further up the binding pocket, makes additional contacts with A156, T157 and K160, thus AM6701 is a non-selective inhibitor
AM6580
-
irreversible inhibitor, i.e. [4-(9H-fluoren-9-yl)-piperazin-1-yl][1,2,3]triazolo[4,5-b]pyridin-1-ylmethanone
benzyl [4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3(2H)-yl)-2-methylphenyl]carbamate
5.12% residual activity at 0.1 mM
jewenol A
reversible inhibitor, catalytic site binding structure, overview
JJKK-048
-
i.e. 4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone
methyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14- tetraenylphosphonofluoridate
-
completely inhibits 4-nitophenyl acetate hydrolysis by pure human MGL at 0.1 mM
N-arachidonyl maleimide
-
potent irreversible inhibitor of MAGL, inhibits in a dose-dependent manner
N-[3-(4-fluorophenyl)-6-oxopyrazolo[5,1-c]pyrido[4,3-e][1,2,4]triazin-7(6H)-yl]-2-(naphthalen-2-yloxy)acetamide
72.3% residual activity at 0.1 mM
N-[4-(1,3-benzothiazol-2-yl)phenyl]-2-(1H-benzotriazol-1-yl)acetamide
14.28% residual activity at 0.1 mM
[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]carbamic acid benzyl ester
-
CAY10499
[4-[bis(1,3-benzodioxol-5-yl)methyl]-1-piperidinyl](1H-1,2,4-triazol-1-yl)methanone
a highly potent selective inhibitor
AM6701
-
MGL inhibition by AM6701 involves a covalent interaction resulting in the enzyme's rapid, selective carbamoylation at its catalytic serine nucleophile (Ser122)
AM6701
-
slowly reversible inhibition, i.e. 5-((biphenyl-4-yl)methyl)-N,N-dimethyl-2H-tetra-zole-2-carboxamide
Disulfiram
-
i.e. tetraethylthiuram disulfide, a compound used to treat alcoholism, inhibition likely through an interaction with cysteine residues Cys208 and/or Cys242, the inhibition is reversible by DTT
JZL184
is more potent than LY2183240. The p-nitrophenyl group fits better in the MAGL cavity than the corresponding substituent of LY2183240
JZL184
MGL-selective inhibitor, represents a ligand with increased steric bulk over AM6701 and 2-arachidonoylglycerol. Extra bulk fills the binding site more completely and one 1,3-benzodioxole moiety makes additional contacts with the lid region of MGL. There is also a weak hydrogen bond from N195 to the p-nitro substituent
JZL184
-
i.e. 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate
methyl arachidonyl fluorophosphonate
irreversible active-site inhibitor of monoglyceride lipase
N-arachidonoylmaleimide
-
inhibits MGL through partial enzyme alkylation at Cys208 and/or Cys242 (Cys242 being favored)
N-arachidonylmaleimide
Cys201 is the crucial residue in MAGL inhibition by N-arachidonylmaleimide
phenylmethylsulfonyl fluoride
PMSF is able to produce an irreversible MAGL-PMSF adduct and hydrofluoric acid (HF), by specifically binding to the hydroxyl group of the serine residue in the active site of the serine protease, thereby inhibiting its enzymatic activity
additional information
-
immunodepletion of the enzyme leads to 50% reduced activity
-
additional information
-
inhibitor screening, molecular docking and modeling, no inhibition of MGL by fatty acid amide hydrolase inhibitors, overview
-
additional information
-
URB754 does not inhibit MAGL activity at concentrations up to 0.100 mM. Assay buffer alone or heat-denatured MAGL protein has no significant activity against 7-hydroxycoumarinyl-arachidonate
-
additional information
-
1-(4-phenylbutanoyl)-(3S)-3-[1(R)-hydroxyethyl]-azetidin-2-one, 1-(5-phenylpentanoyl)-(3S)-3-[1(R)-hydroxyethyl]-azetidin-2-one, 1-(hexa-5-enoyl)-(3S)-3-[1(R)-hydroxyethyl]-azetidin-2-one and 1-(4-phenylbutanoyl)-(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one do not inhibit
-
additional information
diterpenes from Salvia pseudorosmarinus and their activity as inhibitors of monoacylglycerol lipase (MAGL), NMR structure analysis, molecular docking into the catalytic site of the enzyme, overview. No effect by DTT at 0.1 mM and by galloflavin
-
additional information
phenylethanoid glycosides isolated from the n-butanol extract of Cistanche phelypaea aerial parts (collected in March 2012 in the southwest of Algeria) show activity as inhibitors of monoacylglycerol lipase, structure determinations by spectroscopic analyses, including 1D and 2D NMR, and HRESIMS experiments, docking study, overview. No inhibition by galloflavin, apigenin 7-O-beta-D-glucuronopyranoside, and 2-(4-hydroxyphenyl)ethyl alpha-L-rhamnopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->6)]-2-O-acetyl-4-O-(4-coumaroyl)-beta-D-glucopyranoside
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
bovine serum albumin
-
MAGL activity increases with increasing concentration up to 1%
-
additional information
-
dimethyl sulfoxide concentrations up to 10% of the final assay volume have no effect on MAGL activity, the inclusion of dimethyl sulfoxide in the assay can increase the solubility of hydrophobic compounds
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0098
7-hydroxycoumarinyl arachidonate
-
at pH 8 and 25°C, in 10% dimethyl sulfoxide
0.0088
arachidonoyl-7-hydroxy-6-methoxy-4-methylcoumarin ester
recombinant enzyme, in TME buffer, at 37°C
0.01
2-(15-deoxy-DELTA12,14-prostaglandin J2)-glycerol
-
mutant enzyme C242A, at pH 7.4 and 37°C
0.0122
2-(15-deoxy-DELTA12,14-prostaglandin J2)-glycerol
at pH 7.4 and 37°C
0.013
2-(15-deoxy-DELTA12,14-prostaglandin J2)-glycerol
-
mutant enzyme C201A, at pH 7.4 and 37°C
0.015
2-(15-deoxy-DELTA12,14-prostaglandin J2)-glycerol
-
wild type enzyme, at pH 7.4 and 37°C
0.016
2-(15-deoxy-DELTA12,14-prostaglandin J2)-glycerol
-
mutant enzyme C208A, at pH 7.4 and 37°C
0.044
2-arachidonoylglycerol
-
pH and temperature not specified in the publication
0.084
4-Methylumbelliferyl butyrate
mutant enzyme L167Q/L171Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.084
4-Methylumbelliferyl butyrate
mutant enzyme L167Q/L174Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.089
4-Methylumbelliferyl butyrate
mutant enzyme L171Q/L174Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.09
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K160A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.105
4-Methylumbelliferyl butyrate
mutant enzyme L171Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.11
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K226A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.123
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K36A/K226A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.124
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K36A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.136
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.137
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K165A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.162
4-Methylumbelliferyl butyrate
wild type enzyme, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
additional information
additional information
Michaelis-Menten kinetics
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.45
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K165A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.5
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K160A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.5
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K36A/K226A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.63
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K226A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.78
4-Methylumbelliferyl butyrate
mutant enzyme L171Q/L174Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.8
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.85
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K36A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.85
4-Methylumbelliferyl butyrate
mutant enzyme L171Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
0.98
4-Methylumbelliferyl butyrate
mutant enzyme L167Q/L171Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
1.13
4-Methylumbelliferyl butyrate
wild type enzyme, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
1.17
4-Methylumbelliferyl butyrate
mutant enzyme L167Q/L174Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3.3
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K165A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
4.2
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K36A/K226A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
5.5
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K160A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
5.8
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
5.8
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K226A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
6.8
4-Methylumbelliferyl butyrate
mutant enzyme L169S/L176S/K36A, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
7
4-Methylumbelliferyl butyrate
wild type enzyme, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
8
4-Methylumbelliferyl butyrate
mutant enzyme L171Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
8.7
4-Methylumbelliferyl butyrate
mutant enzyme L171Q/L174Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
11.8
4-Methylumbelliferyl butyrate
mutant enzyme L167Q/L171Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
13.8
4-Methylumbelliferyl butyrate
mutant enzyme L167Q/L174Q, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
1.5
umbelliferyl arachidonate
wild type enzyme, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
1.7
umbelliferyl arachidonate
mutant enzyme L169S/L176S, in 20 mM PIPES, pH 7.0, and 150 mM NaCl at 37°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.1
(3R)-1-(3,4-dimethylphenyl)-5-oxo-N-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]pyrrolidine-3-carboxamide
Homo sapiens
IC50 around 0.1 mM, pH and temperature not specified in the publication
0.000039
(3R)-N-(3,5-dimethylphenyl)-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-oxopyrrolidine-3-carboxamide
Homo sapiens
pH and temperature not specified in the publication
0.1
(3S)-N-(1,3-benzodioxol-4-ylmethyl)-1-[4-[(2-chlorobenzyl)oxy]phenyl]-5-oxopyrrolidine-3-carboxamide
Homo sapiens
IC50 around 0.1 mM, pH and temperature not specified in the publication
0.0117
(4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)-methanone
Homo sapiens
pH 7.2, temperature not specified in the publication
0.00851
1-(hexa-5-enoyl)-(3S)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one
Homo sapiens
-
at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
0.0146
1-(hexa-5-enoyl)-(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one
Homo sapiens
-
at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
0.133
1-(pent-4-enoyl)-(3R,4R)-3-[1(R)-(pent-4-enoyloxy)-ethyl]-4-(acetoxy)-azetidin-2-one
Homo sapiens
-
at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
0.00406
1-(pent-4-enoyl)-(3S)-3-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one
Homo sapiens
-
at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
0.00184
1-(pent-4-enoyl)-(3S)-3-[1(R)-(biphenylacetyloxy)-ethyl]-azetidin-2-one
Homo sapiens
-
at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
0.00472
1-(pent-4-enoyl)-(3S)-3-[1(R)-(hexa-5-enoyloxy)-ethyl]-azetidin-2-one
Homo sapiens
-
at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
0.0233
1-(pent-4-enoyl)-(3S)-3-[1(R)-(pent-4-enoyloxy)-ethyl]-azetidin-2-one
Homo sapiens
-
at 37°C for 10 min, in 10 mM Tris-HCl buffer, 1 mM EDTA, 0.1% (w/v) bovine serum albumin, pH 8.0
0.2
12-deacetylsplendidin C
Homo sapiens
above, pH 7.2, temperature not specified in the publication
0.1139
2-(4-hydroxyphenyl)ethyl alpha-L-rhamnopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->6)]-2-O-acetyl-4-O-(4-coumaroyl)-beta-D-glucopyranoside
Homo sapiens
pH 7.4, temperature not specified in the publication
0.088
2-(4-hydroxyphenyl)ethyl alpha-L-rhamnopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->6)]-2-O-acetyl-4-O-beta-D-glucopyranoside
Homo sapiens
pH 7.4, temperature not specified in the publication
0.1174
2-(4-hydroxyphenyl)ethyl alpha-L-rhamnopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->6)]-beta-D-glucopyranoside
Homo sapiens
pH 7.4, temperature not specified in the publication
0.2
2-dehydroxysalvileucanthsin A
Homo sapiens
above, pH 7.2, temperature not specified in the publication
0.1
3-[(4S)-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-2,5-dioxoimidazolidin-4-yl]-N-[(1R,2R)-2-methylcyclohexyl]propanamide
Homo sapiens
IC50 above 0.1 mM, pH and temperature not specified in the publication
0.00021 - 0.0037
4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]piperidine-1-carboxylate
0.000424
benzyl [4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3(2H)-yl)-2-methylphenyl]carbamate
Homo sapiens
pH and temperature not specified in the publication
0.000076
methyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraen-1-ylphosphonofluoridate
Homo sapiens
-
-
0.00078
N-arachidonoyl dopamine
Homo sapiens
-
pH and temperature not specified in the publication
0.000155
N-arachidonyl maleimide
Homo sapiens
-
in 50 mM HEPES buffer, pH 8, 1 mM EDTA, and 10% dimethyl sulfoxide at 25°C for 60 min
0.1
N-[3-(4-fluorophenyl)-6-oxopyrazolo[5,1-c]pyrido[4,3-e][1,2,4]triazin-7(6H)-yl]-2-(naphthalen-2-yloxy)acetamide
Homo sapiens
IC50 above 0.1 mM, pH and temperature not specified in the publication
0.00001
N-[4-(1,3-benzothiazol-2-yl)phenyl]-2-(1H-benzotriazol-1-yl)acetamide
Homo sapiens
pH and temperature not specified in the publication
0.2
pseudorosmaricin
Homo sapiens
above, pH 7.2, temperature not specified in the publication
0.00048 - 0.0011
[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]carbamic acid benzyl ester
0.0000002
[4-[bis(1,3-benzodioxol-5-yl)methyl]-1-piperidinyl](1H-1,2,4-triazol-1-yl)methanone
Homo sapiens
at pH 7.4 and 37°C
0.00021
4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]piperidine-1-carboxylate
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, without Triton X-100
0.0017
4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]piperidine-1-carboxylate
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, in the presence of 0.2% (m/v) Triton X-100
0.0037
4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]piperidine-1-carboxylate
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, in the presence of 0.2% (m/v) Triton X-100
0.0000009
AM6701
Homo sapiens
-
native enzyme, in 50 mM Tris-HCl (pH 7.4) containing 8% DMSO, at room temperature
0.0000017
AM6701
Homo sapiens
-
recombinant enzyme, in 50 mM Tris-HCl (pH 7.4) containing 8% DMSO, at room temperature
0.0001
AM6702
Homo sapiens
-
native enzyme, in 50 mM Tris-HCl (pH 7.4) containing 8% DMSO, at room temperature
0.0028
AM6702
Homo sapiens
-
native enzyme, in 50 mM Tris-HCl (pH 7.4) containing 8% DMSO, at room temperature
0.000033
methyl arachidonyl fluorophosphonate
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, without Triton X-100
0.000062
methyl arachidonyl fluorophosphonate
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, in the presence of 0.2% (m/v) Triton X-100
0.00016
methyl arachidonyl fluorophosphonate
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, in the presence of 0.2% (m/v) Triton X-100
0.0000091
N-arachidonylmaleimide
Homo sapiens
-
native enzyme, in 50 mM Tris-HCl (pH 7.4) containing 8% DMSO, at room temperature
5.38
N-arachidonylmaleimide
Homo sapiens
mutant C201A, at 37°C for 10 min, pH 8.0, in 50 mM Tris buffer
6.11
N-arachidonylmaleimide
Homo sapiens
mutant C242A, at 37°C for 10 min, pH 8.0, in 50 mM Tris buffer
6.27
N-arachidonylmaleimide
Homo sapiens
wild-type, at 37°C for 10 min, pH 8.0, in 50 mM Tris buffer
6.48
N-arachidonylmaleimide
Homo sapiens
mutant C208A/C242A, at 37°C for 10 min, pH 8.0, in 50 mM Tris buffer
6.64
N-arachidonylmaleimide
Homo sapiens
mutant C208A, at 37°C for 10 min, pH 8.0, in 50 mM Tris buffer
0.005
N-benzoylthiocarbamic cyclohexylethyl ester
Homo sapiens
-
using 4-nitophenyl acetate as a substrate
0.02
N-benzoylthiocarbamic cyclohexylethyl ester
Homo sapiens
-
using 2-oleoylglycerol as a substrate
0.0032
phenylmethylsulfonyl fluoride
Homo sapiens
versus 7-4-nitrophenylacetate, pH 8.0-9.0, 37°C, recombinant enzyme
0.0033
phenylmethylsulfonyl fluoride
Homo sapiens
versus 7-hydroxycoumarinyl arachidonate, pH 8.0-9.0, 37°C, recombinant enzyme
0.0031
URB602
Homo sapiens
-
in 50 mM HEPES buffer, pH 8, 1 mM EDTA, and 10% dimethyl sulfoxide at 25°C for 60 min
0.00048
[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]carbamic acid benzyl ester
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, in the presence of 0.2% (m/v) Triton X-100
0.00061
[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]carbamic acid benzyl ester
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, without Triton X-100
0.0011
[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]carbamic acid benzyl ester
Homo sapiens
-
at 37°C, pH 7.0, incubation time of 15 min, in the presence of 0.2% (m/v) Triton X-100
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
physiological function
additional information
evolution
human monoacylglycerol lipase (MAGL) is a soluble serine hydrolase that belongs to the alpha/beta hydrolase fold superfamily
evolution
the GxSxS motif is conserved in monoacylglycerol lipases (MAGLs)
malfunction
-
disruption of MAGL expression and activity impairs cancer pathogenicity. impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity
malfunction
deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in tumor-associated macrophages. MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells, and contributes to lipid accumulation. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models
physiological function
-
monoacylglycerol lipase (MAGL) regulates a fatty acid network that promotes cancer pathogenesis. MAGL, through hydrolysis of monoacylglycerols, controls free fatty acid levels in cancer cells
physiological function
human monoacylglycerol lipase (MAGL) regulates 2-arachidonoyl glycerol level in the endocannabinoid system, which is implicated in a number of severe diseases. It is the main enzyme responsible for inactivating endocannabinoid agonist 2-arachidonoylglycerol (2-AG) for central CB1 and peripheral CB2 receptors and consequently for reducing its (patho)physiological effects. MAGL modulates endocannabinoid signaling in vivo by hydrolysis of 2-AG to arachidonic acid and glycerol
physiological function
MAGL is a serine hydrolase that cleaves monoacyglycerols into fatty acids and glycerol. In particular, MAGL is the lipolytic enzyme that is mainly responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol, which is a neurotransmitter and an important intermediate in lipid metabolism involved in many physiological processes. Moreover, the intensified production of fatty acids in cancer cells, generated by MAGL activity, increases the formation of protumorigenic signaling molecules
physiological function
monoacylglycerol lipase (MGLL) regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression. Analysis of mechanism underlying MGLL-CB2-regulated macrophage activation using in vitro and mouse models with pharmacological or genetic manipulation. Modulation of MGLL-CB2 axis in macrophages might be a promising strategy for cancer treatment. Macrophage MGLL inhibits tumor progression via CD8+ T cells, mechanism, overview. MGLL regulates macrophage activity via CB2/TLR4 interaction
physiological function
the serine hydrolase monoacylglycerol lipase (MGL) functions as the main metabolizing enzyme of 2-arachidonoyl glycerol, an endocannabinoid signaling lipid. Monoacylglycerol lipase is largely responsible for the catalytic inactivation of the endocannabinoid signaling lipid, 2-arachidonoylglycerol, and regulates a fatty acid network that promotes tumorigenesis
additional information
a network of aromatic interactions and hydrogen bonds regulates hMGL active-inactive state interconversion. Specific inter-residue interactions within hMGL modulate the enzymes function and implicate transitions between active (open) and inactive (closed) states of the hMGL lid domain in controlling substrate access to the enzymes active site. The residues Ser122, His269, and Asp239 form the catalytic triad, hMGL structure-function correlations, overview
additional information
-
a network of aromatic interactions and hydrogen bonds regulates hMGL active-inactive state interconversion. Specific inter-residue interactions within hMGL modulate the enzymes function and implicate transitions between active (open) and inactive (closed) states of the hMGL lid domain in controlling substrate access to the enzymes active site. The residues Ser122, His269, and Asp239 form the catalytic triad, hMGL structure-function correlations, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ABHD6_HUMAN
337
1
38331
Swiss-Prot
Secretory Pathway (Reliability: 2)
ABD12_HUMAN
398
1
45097
Swiss-Prot
other Location (Reliability: 3)
ABHD2_HUMAN
425
0
48315
Swiss-Prot
other Location (Reliability: 3)
ABHGA_HUMAN
558
2
63243
Swiss-Prot
Mitochondrion (Reliability: 5)
LIPS_HUMAN
1076
0
116598
Swiss-Prot
other Location (Reliability: 3)
MGLL_HUMAN
303
0
33261
Swiss-Prot
other Location (Reliability: 2)
A0A5F9ZH71_HUMAN
241
0
27640
TrEMBL
other Location (Reliability: 2)
I3L294_HUMAN
159
0
18033
TrEMBL
other Location (Reliability: 2)
A0A5F9ZH28_HUMAN
169
0
18980
TrEMBL
other Location (Reliability: 2)
A0A5F9ZGT4_HUMAN
250
0
28487
TrEMBL
other Location (Reliability: 2)
B3KNX9_HUMAN
339
0
38193
TrEMBL
Secretory Pathway (Reliability: 3)
A0A5F9ZHG5_HUMAN
120
0
13486
TrEMBL
other Location (Reliability: 2)
A0A5F9ZH49_HUMAN
228
0
25912
TrEMBL
other Location (Reliability: 2)
A8K0A4_HUMAN
558
2
63259
TrEMBL
Mitochondrion (Reliability: 5)
A8K8W7_HUMAN
1076
0
116584
TrEMBL
other Location (Reliability: 3)
A0A5F9ZHQ8_HUMAN
295
0
33240
TrEMBL
other Location (Reliability: 2)
A0A5F9ZGW7_HUMAN
179
0
20196
TrEMBL
other Location (Reliability: 2)
A0A5F9ZHM3_HUMAN
176
0
19803
TrEMBL
other Location (Reliability: 2)
I3L1V0_HUMAN
194
0
21023
TrEMBL
other Location (Reliability: 3)
A0A5F9ZHH2_HUMAN
227
0
25894
TrEMBL
other Location (Reliability: 2)
I3L440_HUMAN
105
0
11797
TrEMBL
other Location (Reliability: 2)
A0A0G2JJD3_HUMAN
601
3
67519
TrEMBL
Mitochondrion (Reliability: 3)
Q5T712_HUMAN
187
2
21231
TrEMBL
Secretory Pathway (Reliability: 2)
A0A1U9X777_HUMAN
558
2
63243
TrEMBL
Mitochondrion (Reliability: 5)
A0A5F9ZHE8_HUMAN
143
0
16768
TrEMBL
other Location (Reliability: 1)
I3L206_HUMAN
216
0
24885
TrEMBL
other Location (Reliability: 2)
A0A5F9ZGZ9_HUMAN
153
0
17287
TrEMBL
other Location (Reliability: 2)
A0A5F9ZHQ0_HUMAN
210
0
24047
TrEMBL
other Location (Reliability: 2)
A0A5F9ZHF0_HUMAN
151
0
17237
TrEMBL
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
33000
35000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
additional information
additional information
simultaneous NMR detection of both active and inactive hMGL states in solution
additional information
-
simultaneous NMR detection of both active and inactive hMGL states in solution
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
apoenzyme alone or in complex with inhibitor SAR629, in 50 mM MES (pH 6.0) and 40% (v/v) 2-methyl-pentane-2,4-diol, at 4°C
-
by the hanging drop method and under oil crystallization, native enzyme or selenomethionyl derivative, at 2.2 A resolution. Belongs to I222 space group, with two molecules per asymmetric unit. Docking of 2-arachidonoylglycerol highlights a hydrophobic and a hydrophilic cavity that accommodate the lipid into the catalytic site
in complex with methyl arachidonyl fluorophosphonate, hanging drop vapor diffusion method, using 6-10% (w/v) PEGMME 5000, 100 mM Na-MES pH 6.0, 0.2% (w/v) glucopyranoside, at 22°C
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C201A
C208A
C215A
-
the mutation does not affect MGL hydrolytic activity and displays heightened N-arachidonylmaleimide sensitivity
C242A
C249A
-
the mutation does not affect MGL hydrolytic activity and displays reduced N-arachidonylmaleimide sensitivity
G111S
site-directed mutagenesis by overlap extension PCR, inactive mutant
G115S
site-directed mutagenesis by overlap extension PCR, inactive mutant
H103A
site-directed mutagenesis, the mutant shows 20fold reduced catalytic efficiency compared to wild-type
H269A
site-directed mutagenesis, structural comparison to the wild-type enzyme by NMR spectrometry
H272A
site-directed mutagenesis, the mutant shows 13fold reduced catalytic efficiency compared to wild-type
H272S
site-directed mutagenesis, the mutant shows 58fold reduced catalytic efficiency compared to wild-type
H272Y
site-directed mutagenesis, the muant shows 12fold reduced catalytic efficiency compared to wild-type
H49A
site-directed mutagenesis, the mutant shows 5fold reduced catalytic efficiency compared to wild-type
H54A
site-directed mutagenesis, structural comparison to the wild-type enzyme by NMR spectrometry, the mutant shows a dramatic 25000fold loss in hMGL catalytic efficiency compared to wild-type
L167Q/L171Q
the mutant shows increased catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
L167Q/L174Q
the mutant shows increased catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
L169S/L176S
L169S/L176S/K160A
the mutant shows reduced catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
L169S/L176S/K165A
the mutant shows reduced catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
L169S/L176S/K226A
the mutant shows reduced catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
L169S/L176S/K36A
the mutant shows about wild type catalytic efficiency with 4-methylumbelliferyl butyrate
L169S/L176S/K36A/K226A
the mutant shows reduced catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
L171Q
the mutant shows about wild type catalytic efficiency with 4-methylumbelliferyl butyrate
L171Q/L174Q
the mutant shows increased catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
S113A
site-directed mutagenesis by overlap extension PCR, inactive mutant
S122C
site-directed mutagenesis, structural comparison to the wild-type enzyme by NMR spectrometry
additional information
C201A
-
the mutation causes a significant reduction in overall activity particularly skewing the balanced hydrolysis of monoacyl glycerol isomers to favor the 2-isomer over the 1-isomer
C208A
-
the mutation causes a significant reduction in overall activity particularly skewing the balanced hydrolysis of monoacyl glycerol isomers to favor the 2-isomer over the 1-isomer
C242A
-
the mutation causes a significant reduction in overall activity particularly skewing the balanced hydrolysis of monoacyl glycerol isomers to favor the 2-isomer over the 1-isomer
L169S/L176S
the mutant shows reduced catalytic efficiency with 4-methylumbelliferyl butyrate and increased catalytic efficiency with umbelliferyl arachidonate compared to the wild type enzyme
L169S/L176S
the mutant shows reduced catalytic efficiency with 4-methylumbelliferyl butyrate compared to the wild type enzyme
L169S/L176S
site-directed mutagenesis, hMGL function is not significantly compromised by the mutation, structural comparison to the wild-type enzyme by NMR spectrometry
additional information
-
construction of a HeLa cell line, HeLa-MGLi, with stable repression of enzyme expression by RNAi silencing, the cells show 20% of wild-type cell line enzyme activity
additional information
computational modeling shows that amino acid changes of the GxSxG motif in AtMAGL6 alters the nucleophilic elbow structure, which is the active site of MAGLs. Mutating the GxSxG motif in the recombinant maltose binding protein (MBP):AtMAGL6 protein to SxSxG, GxAxG, and GxSxS motifs completely demolishes the activities of the mutant MAGL
additional information
the transgene of human MGLL in macrophages largely prolonges the survival of MC-38 tumor-bearing mice
additional information
-
the transgene of human MGLL in macrophages largely prolonges the survival of MC-38 tumor-bearing mice
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
58
the midpoint of the melting transition is calculated to be 58°C for wild type enzyme
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, 50 mM Tris buffer, 200 mM NaCl, 0.1% lauryl dimethylamine N-oxide, pH 9.5
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
MAGL-His6 protein purified on nickel-nitrilotriacetic acid column, more than 90% pure
-
recombinant His6-tagged and streptavidin-tagged enzyme from Escherichia coli to homogeneity by Strep-tag targeting afffinity chromatography and nickel affinity chromatography
-
recombinant MBP-tagged wild-type and mutant enzymes from Escherichia coli by amylose affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 and Rosetta cells. Expression in the baculovirus expression system produced only insoluble, aggregated protein
functional overexpression of His6-tagged and streptavidin-tagged enzyme in Escherichia coli as soluble protein in the supernatant
-
gene MGLL, sequence comparisons and phylogenetic analysis and tree, recombinant expression of MBP-tagged wild-type and mutant enzymes in Escherichia coli
into vector pColdII with a His6 tag at the N-terminus. Expression in Escherichia coli BL21 (DE3) competent cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
monoacylglycerol lipase is highly expressed in aggressive human cancer cells and primary tumors
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
enzyme MGLL in tumor-associated macrophages predicts the survival of colorectal cancer patients
drug development
medicine
drug development
-
the enzyme is a target for design of potent and selective inhibitors
drug development
potent MGL inhibitors with selectivity over FAAH may be realized by exploiting structural difference as well as the binding sub-pocket, increased volume around the catalytic site, and potential hydrogen-bonding opportunities
drug development
structure of MAGL paves the way for future medicinal chemistry works aimed at the design of new drugs exploiting 2-arachidonoylglycerol transmission. MAGL is a hot therapeutic target, because the design of selective and potent inhibitors can provide unique tools to interfere with 2-arachidonoylglycerol degradation and to finely modulate the endocannabinoid signal
medicine
enzyme MAGL represents a potential target to treat diverse pathological conditions, including cancer
medicine
expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Monoacylglycerol lipase is a switch for CB2/TLR4-dependent macrophage activation and a potential target for cancer therapy. Modulation of MGLL-CB2 axis in macrophages might be a promising strategy for cancer treatment
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Somma-Delpero, C.; Valette, A.; Lepetit-Thevenin, J.; Nobili, O.; Boyer, J.; Verine, A.
Purification and properties of a monoacylglycerol lipase in human erythrocytes
Biochem. J.
312
519-525
1995
Homo sapiens
Dinh, T.P.; Kathuria, S.; Piomelli, D.
RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol
Mol. Pharmacol.
66
1260-1264
2004
Homo sapiens, Rattus norvegicus
Labar, G.; Bauvois, C.; Muccioli, G.G.; Wouters, J.; Lambert, D.M.
Disulfiram is an inhibitor of human purified monoacylglycerol lipase, the enzyme regulating 2-arachidonoylglycerol signaling
Chembiochem
8
1293-1297
2007
Homo sapiens
Chon, S.H.; Zhou, Y.X.; Dixon, J.L.; Storch, J.
Intestinal monoacylglycerol metabolism: developmental and nutritional regulation of monoacylglycerol lipase and monoacylglycerol acyltransferase
J. Biol. Chem.
282
33346-33357
2007
Homo sapiens, Mus musculus, Mus musculus C57BL/6
Saario, S.M.; Poso, A.; Juvonen, R.O.; Jaervinen, T.; Salo-Ahen, O.M.
Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system
J. Med. Chem.
49
4650-4656
2006
Homo sapiens, Rattus norvegicus
Zvonok, N.; Pandarinathan, L.; Williams, J.; Johnston, M.; Karageorgos, I.; Janero, D.R.; Krishnan, S.C.; Makriyannis, A.
Covalent inhibitors of human monoacylglycerol lipase: ligand-assisted characterization of the catalytic site by mass spectrometry and mutational analysis
Chem. Biol.
15
854-862
2008
Homo sapiens
Muccioli, G.G.; Labar, G.; Lambert, D.M.
CAY10499, a novel monoglyceride lipase inhibitor evidenced by an expeditious MGL assay
ChemBioChem
9
2704-2710
2008
Homo sapiens
Zvonok, N.; Williams, J.; Johnston, M.; Pandarinathan, L.; Janero, D.R.; Li, J.; Krishnan, S.C.; Makriyannis, A.
Full mass spectrometric characterization of human monoacylglycerol lipase generated by large-scale expression and single-step purification
J. Proteome Res.
7
2158-2164
2008
Rattus norvegicus (Q8R431), Homo sapiens (Q99685), Homo sapiens
Holtfrerich, A.; Makharadze, T.; Lehr, M.
High-performance liquid chromatography assay with fluorescence detection for the evaluation of inhibitors against human recombinant monoacylglycerol lipase
Anal. Biochem.
399
218-224
2010
Homo sapiens, Mus musculus, Rattus norvegicus
Wang, Y.; Chanda, P.; Jones, P.G.; Kennedy, J.D.
A fluorescence-based assay for monoacylglycerol lipase compatible with inhibitor screening
Assay Drug Dev. Technol.
6
387-393
2008
Homo sapiens
Labar, G.; Bauvois, C.; Borel, F.; Ferrer, J.L.; Wouters, J.; Lambert, D.M.
Crystal structure of the human monoacylglycerol lipase, a key actor in endocannabinoid signaling
ChemBioChem
11
218-227
2010
Homo sapiens (Q99685), Homo sapiens
Vandevoorde, S.
Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors
Curr. Top. Med. Chem.
8
247-267
2008
Homo sapiens, Mus musculus, Rattus norvegicus
Bowman, A.L.; Makriyannis, A.
Refined homology model of monoacylglycerol lipase: toward a selective inhibitor
J. Comput. Aided Mol. Des.
23
799-806
2009
Homo sapiens (Q99685)
Feledziak, M.; Michaux, C.; Urbach, A.; Labar, G.; Muccioli, G.G.; Lambert, D.M.; Marchand-Brynaert, J.
beta-Lactams derived from a carbapenem chiron are selective inhibitors of human fatty acid amide hydrolase versus human monoacylglycerol lipase
J. Med. Chem.
52
7054-7068
2009
Homo sapiens
Bjoerklund, E.; Noren, E.; Nilsson, J.; Fowler, C.J.
Inhibition of monoacylglycerol lipase by troglitazone, N-arachidonoyl dopamine and the irreversible inhibitor JZL184: comparison of two different assays
Br. J. Pharmacol.
161
1512-1526
2010
Homo sapiens, Rattus norvegicus
Nomura, D.K.; Long, J.Z.; Niessen, S.; Hoover, H.S.; Ng, S.W.; Cravatt, B.F.
Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis
Cell
140
49-61
2010
Homo sapiens
Bertrand, T.; Auge, F.; Houtmann, J.; Rak, A.; Vallee, F.; Mikol, V.; Berne, P.; Michot, N.; Cheuret, D.; Hoornaert, C.; Mathieu, M.
Structural basis for human monoglyceride lipase inhibition
J. Mol. Biol.
396
663-673
2010
Homo sapiens
Karageorgos, I.; Tyukhtenko, S.; Zvonok, N.; Janero, D.R.; Sallum, C.; Makriyannis, A.
Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism
Mol. Biosyst.
6
1381-1388
2010
Homo sapiens
Schalk-Hihi, C.; Schubert, C.; Alexander, R.; Bayoumy, S.; Clemente, J.C.; Deckman, I.; DesJarlais, R.L.; Dzordzorme, K.C.; Flores, C.M.; Grasberger, B.; Kranz, J.K.; Lewandowski, F.; Liu, L.; Ma, H.; Maguire, D.; Macielag, M.J.; McDonnell, M.E.; Mezzasalma Haarlander, T.; Miller, R.; Milligan, C.; R, R.e.
Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A resolution
Protein Sci.
20
670-683
2011
Homo sapiens (Q99685), Homo sapiens
Karageorgos, I.; Wales, T.E.; Janero, D.R.; Zvonok, N.; Vemuri, V.K.; Engen, J.R.; Makriyannis, A.
Active-site inhibitors modulate the dynamic properties of human monoacylglycerol lipase: a hydrogen exchange mass spectrometry study
Biochemistry
52
5016-5026
2013
Homo sapiens
Afzal, O.; Kumar, S.; Kumar, R.; Firoz, A.; Jaggi, M.; Bawa, S.
Docking based virtual screening and molecular dynamics study to identify potential monoacylglycerol lipase inhibitors
Bioorg. Med. Chem. Lett.
24
3986-3996
2014
Homo sapiens (Q99685), Homo sapiens
Li, C.; Vilches-Flores, A.; Zhao, M.; Amiel, S.A.; Jones, P.M.; Persaud, S.J.
Expression and function of monoacylglycerol lipase in mouse beta-cells and human islets of Langerhans
Cell. Physiol. Biochem.
30
347-358
2012
Homo sapiens, Mus musculus
Laitinen, T.; Navia-Paldanius, D.; Rytilahti, R.; Marjamaa, J.J.; Ka?izkova, J.; Parkkari, T.; Pantsar, T.; Poso, A.; Laitinen, J.T.; Savinainen, J.R.
Mutation of Cys242 of human monoacylglycerol lipase disrupts balanced hydrolysis of 1- and 2-monoacylglycerols and selectively impairs inhibitor potency
Mol. Pharmacol.
85
510-519
2014
Homo sapiens
Savinainen, J.R.; Kansanen, E.; Pantsar, T.; Navia-Paldanius, D.; Parkkari, T.; Lehtonen, M.; Laitinen, T.; Nevalainen, T.; Poso, A.; Levonen, A.L.; Laitinen, J.T.
Robust hydrolysis of prostaglandin glycerol esters by human monoacylglycerol lipase (MAGL)
Mol. Pharmacol.
86
522-535
2014
Homo sapiens (Q99685), Homo sapiens
Chen, H.; Tian, R.; Ni, Z.; Zhang, Z.; Chen, H.; Guo, Q.; Saier, M.H.
Conformational transition pathway in the inhibitor binding process of human monoacylglycerol lipase
Protein J.
33
503-511
2014
Homo sapiens
Lauria, S.; Casati, S.; Ciuffreda, P.
Synthesis and characterization of a new fluorogenic substrate for monoacylglycerol lipase and application to inhibition studies
Anal. Bioanal. Chem.
407
8163-8167
2015
Homo sapiens (Q99685), Homo sapiens
Kim, R.; Suh, M.
The GxSxG motif of Arabidopsis monoacylglycerol lipase (MAGL6 and MAGL8) is essential for their enzyme activities
Appl. Biol. Chem.
59
833-840
2016
Arabidopsis thaliana (O49284), Arabidopsis thaliana (O80959), Arabidopsis thaliana (Q8H133), Homo sapiens (Q99685)
-
De Leo, M.; Huallpa, C.G.; Alvarado, B.; Granchi, C.; Poli, G.; De Tommasi, N.; Braca, A.
New diterpenes from Salvia pseudorosmarinus and their activity as inhibitors of monoacylglycerol lipase (MAGL)
Fitoterapia
130
251-258
2018
Homo sapiens (Q99685)
Tyukhtenko, S.; Karageorgos, I.; Rajarshi, G.; Zvonok, N.; Pavlopoulos, S.; Janero, D.R.; Makriyannis, A.
Specific inter-residue interactions as determinants of human monoacylglycerol lipase catalytic competency a role for global conformational chanages
J. Biol. Chem.
291
2556-2565
2016
Homo sapiens (Q99685), Homo sapiens
Xiang, W.; Shi, R.; Kang, X.; Zhang, X.; Chen, P.; Zhang, L.; Hou, A.; Wang, R.; Zhao, Y.; Zhao, K.; Liu, Y.; Ma, Y.; Luo, H.; Shang, S.; Zhang, J.; He, F.; Yu, S.; Gan, L.; Shi, C.; Li, Y.; Yang, W.; Liang, H.; Miao, H.
Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression
Nat. Commun.
9
2574
2018
Mus musculus (O35678), Homo sapiens (Q99685), Homo sapiens
EXTERNAL LINKS (specific for EC-Number 3.1.1.23)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
