MGLL

Summary

MGLL (monoglyceride lipase, HGNC:17038) is a protein-coding gene on chromosome 3q21.3, encoding Monoglyceride lipase (Q99685). Converts monoacylglycerides to free fatty acids and glycerol.

This gene encodes a serine hydrolase of the AB hydrolase superfamily that catalyzes the conversion of monoacylglycerides to free fatty acids and glycerol. The encoded protein plays a critical role in several physiological processes including pain and nociperception through hydrolysis of the endocannabinoid 2-arachidonoylglycerol. Expression of this gene may play a role in cancer tumorigenesis and metastasis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 11343 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 47 total
• GTEx eGene: eQTL in 26 tissues, sQTL in 26 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug; 4 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 0.98 (loss-of-function intolerant), LOEUF 0.50 (moderately constrained)
• MANE Select transcript: NM_007283
• Interaction hub: 2,106 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17038
Approved symbol	MGLL
Name	monoglyceride lipase
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	HU-K5, MGL, MAGL
Ensembl gene	ENSG00000074416
Ensembl biotype	protein_coding
OMIM	609699
Entrez	11343

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 29 protein_coding, 14 nonsense_mediated_decay, 6 protein_coding_CDS_not_defined

MANE Select: ENST00000265052

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 2, TSL 5: 4

ENST00000265052, ENST00000398101, ENST00000398104, ENST00000453507, ENST00000465597, ENST00000476654, ENST00000476682, ENST00000479967, ENST00000487473, ENST00000493611, ENST00000494830, ENST00000496306, ENST00000648300, ENST00000864851, ENST00000864852, ENST00000864853, ENST00000864854, ENST00000864855, ENST00000864856, ENST00000959996, ENST00000959997, ENST00001005249, ENST00001005250, ENST00001005251, ENST00001005252, ENST00001005253, ENST00001005254, ENST00001005255, ENST00001040426, ENST00001040427, ENST00001040428, ENST00001040429, ENST00001040430, ENST00001040431, ENST00001040432, ENST00001040433, ENST00001040434, ENST00001040435, ENST00001040436, ENST00001040437, ENST00001040438, ENST00001040439, ENST00001040440, ENST00001040441, ENST00001040442, ENST00001040443, ENST00001040444, ENST00001115982, ENST00001144021

RefSeq mRNA: 10 — MANE Select: NM_007283 NM_001003794, NM_001256585, NM_001388312, NM_001388313, NM_001388314, NM_001388315, NM_001388316, NM_001388317, NM_001388318, NM_007283

CCDS: CCDS43148, CCDS46902, CCDS58852

Canonical transcript exons

ENST00000265052 — 8 exons

Exon	Start	End
ENSE00000968265	127710576	127710665
ENSE00001881088	127689066	127692323
ENSE00003468769	127694975	127695190
ENSE00003471817	127721053	127721163
ENSE00003573885	127722430	127722566
ENSE00003619631	127821694	127821838
ENSE00003785570	127781789	127781895
ENSE00003917324	127822309	127822515

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.5422 / max 594.0582, expressed in 1621 samples.

Highest expression (Bgee): decidua, ileal mucosa, mucosa of transverse colon, lower esophagus mucosa, subcutaneous adipose tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MGLL is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 26 tissues and its splicing (sQTL) in 26 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 52 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	sqtl	2.0e-19	+0.74	3:127715072:A:G
Cells EBV-transformed lymphocytes	eqtl	6.7e-19	+0.48	3:127755187:G:A
Cells Cultured fibroblasts	eqtl	7.8e-17	-0.28	3:127768537:G:T
Adipose Subcutaneous	sqtl	1.6e-15	+0.32	3:127710724:C:G
Nerve Tibial	sqtl	6.0e-14	+0.42	3:127713762:T:C
Esophagus Mucosa	eqtl	1.0e-13	-0.62	3:127847848:T:C
Artery Tibial	eqtl	9.4e-12	+0.32	3:127803838:G:C
Adipose Visceral Omentum	sqtl	1.0e-10	+0.36	3:127721240:A:C
Muscle Skeletal	sqtl	2.1e-10	+0.39	3:127727528:T:C
Skin Sun Exposed Lower leg	sqtl	7.4e-10	+0.35	3:127706140:C:T
Spleen	sqtl	1.2e-09	+1.05	3:127715072:A:G
Lung	sqtl	1.8e-09	+0.61	3:127715072:A:G
Cells EBV-transformed lymphocytes	sqtl	4.0e-09	+0.38	3:127711082:G:A
Artery Tibial	sqtl	1.8e-08	-0.39	3:127689339:C:T
Nerve Tibial	eqtl	2.8e-08	+0.19	3:127813405:T:C
Colon Transverse	sqtl	7.6e-07	-0.24	3:127716963:T:C
Esophagus Muscularis	sqtl	1.1e-05	+0.34	3:127712800:C:T
Brain Cerebellum	eqtl	1.8e-05	+0.21	3:127747027:G:A
Breast Mammary Tissue	sqtl	4.9e-05	-0.26	3:127714699:C:T
Artery Aorta	eqtl	5.7e-05	+0.33	3:127791441:T:C

FANTOM5 promoters

showing 10 of 25 alternative TSS:

Promoter ID	TPM avg	Samples expressed
44410	28.1948	1472
44402	5.4620	1214
44411	3.6176	1269
44405	0.7376	381
44403	0.6287	359
44412	0.5636	313
44404	0.4936	227
44415	0.3884	191
44406	0.3874	198
44408	0.3530	178

Top tissues by expression

showing 100 of 302 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	98.85	gold quality
ileal mucosa	UBERON:0000331	98.42	gold quality
mucosa of transverse colon	UBERON:0004991	97.98	gold quality
lower esophagus mucosa	UBERON:0035834	97.89	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.78	gold quality
adipose tissue	UBERON:0001013	97.70	gold quality
apex of heart	UBERON:0002098	97.41	gold quality
connective tissue	UBERON:0002384	97.35	gold quality
right frontal lobe	UBERON:0002810	97.35	gold quality
epithelium of esophagus	UBERON:0001976	97.27	gold quality
endothelial cell	CL:0000115	97.17	gold quality
esophagus squamous epithelium	UBERON:0006920	97.15	gold quality
olfactory bulb	UBERON:0002264	97.01	gold quality
pericardium	UBERON:0002407	96.95	gold quality
rectum	UBERON:0001052	96.81	gold quality
pharyngeal mucosa	UBERON:0000355	96.77	gold quality
lower lobe of lung	UBERON:0008949	96.73	gold quality
prefrontal cortex	UBERON:0000451	96.71	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.68	gold quality
cingulate cortex	UBERON:0003027	96.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.62	gold quality
anterior cingulate cortex	UBERON:0009835	96.60	gold quality
mouth mucosa	UBERON:0003729	96.59	gold quality
oral cavity	UBERON:0000167	96.56	gold quality
vena cava	UBERON:0004087	96.56	gold quality
minor salivary gland	UBERON:0001830	96.55	gold quality
frontal cortex	UBERON:0001870	96.54	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.54	gold quality
frontal lobe	UBERON:0016525	96.53	gold quality
cerebellar hemisphere	UBERON:0002245	96.48	gold quality
cerebellar cortex	UBERON:0002129	96.45	gold quality
esophagus mucosa	UBERON:0002469	96.43	gold quality
amygdala	UBERON:0001876	96.42	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.40	gold quality
omental fat pad	UBERON:0010414	96.39	gold quality
saliva-secreting gland	UBERON:0001044	96.34	gold quality
peritoneum	UBERON:0002358	96.33	gold quality
cerebellum	UBERON:0002037	96.32	gold quality
transverse colon	UBERON:0001157	96.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.27	gold quality
neocortex	UBERON:0001950	96.26	gold quality
superior frontal gyrus	UBERON:0002661	96.22	gold quality
temporal lobe	UBERON:0001871	96.12	gold quality
vein	UBERON:0001638	96.10	gold quality
parietal lobe	UBERON:0001872	96.09	gold quality
putamen	UBERON:0001874	96.09	gold quality
caudate nucleus	UBERON:0001873	96.03	gold quality
postcentral gyrus	UBERON:0002581	96.02	gold quality
adult organism	UBERON:0007023	96.00	gold quality
skin of hip	UBERON:0001554	95.98	gold quality
entorhinal cortex	UBERON:0002728	95.97	gold quality
saphenous vein	UBERON:0007318	95.95	gold quality
nipple	UBERON:0002030	95.92	gold quality
gingiva	UBERON:0001828	95.85	gold quality
stromal cell of endometrium	CL:0002255	95.79	gold quality
trachea	UBERON:0003126	95.78	gold quality
cerebral cortex	UBERON:0000956	95.76	gold quality
mammalian vulva	UBERON:0000997	95.74	gold quality
squamous epithelium	UBERON:0006914	95.71	gold quality
cortical plate	UBERON:0005343	95.62	gold quality
parotid gland	UBERON:0001831	95.61	gold quality
gingival epithelium	UBERON:0001949	95.56	gold quality
upper lobe of lung	UBERON:0008948	95.53	gold quality
telencephalon	UBERON:0001893	95.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.52	gold quality
body of tongue	UBERON:0011876	95.51	gold quality
gall bladder	UBERON:0002110	95.45	gold quality
right lobe of liver	UBERON:0001114	95.44	gold quality
upper lobe of left lung	UBERON:0008952	95.43	gold quality
colonic mucosa	UBERON:0000317	95.37	gold quality
tibialis anterior	UBERON:0001385	95.31	gold quality
esophagus	UBERON:0001043	95.30	gold quality
occipital lobe	UBERON:0002021	95.27	gold quality
metanephros cortex	UBERON:0010533	95.14	gold quality
primary visual cortex	UBERON:0002436	95.11	gold quality
mammary duct	UBERON:0001765	95.05	gold quality
CA1 field of hippocampus	UBERON:0003881	95.01	gold quality
renal medulla	UBERON:0000362	94.99	gold quality
dorsal root ganglion	UBERON:0000044	94.98	gold quality
orbitofrontal cortex	UBERON:0004167	94.97	gold quality
synovial joint	UBERON:0002217	94.96	gold quality
cardiac ventricle	UBERON:0002082	94.92	gold quality
penis	UBERON:0000989	94.91	gold quality
heart left ventricle	UBERON:0002084	94.90	gold quality
colonic epithelium	UBERON:0000397	94.82	gold quality
Ammon’s horn	UBERON:0001954	94.82	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.72	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.71	gold quality
adult mammalian kidney	UBERON:0000082	94.70	gold quality
colon	UBERON:0001155	94.49	gold quality
large intestine	UBERON:0000059	94.48	gold quality
heart right ventricle	UBERON:0002080	94.48	gold quality
tongue squamous epithelium	UBERON:0006919	94.44	gold quality
liver	UBERON:0002107	94.41	gold quality
nucleus accumbens	UBERON:0001882	94.36	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.36	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.36	gold quality
thoracic mammary gland	UBERON:0005200	94.34	gold quality
mammary gland	UBERON:0001911	94.29	gold quality
tibial nerve	UBERON:0001323	94.24	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-7381	yes	927.42
E-GEOD-75688	yes	873.96
E-MTAB-6075	yes	173.58
E-HCAD-5	yes	46.64
E-CURD-112	yes	34.73
E-MTAB-8142	yes	25.24
E-GEOD-125970	yes	22.82
E-HCAD-6	yes	18.84
E-MTAB-9067	yes	12.16
E-CURD-114	yes	11.70
E-GEOD-84465	yes	11.66
E-MTAB-8498	yes	8.66
E-MTAB-10596	no	224.52
E-MTAB-10137	no	4.62
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Frontal cortex	tissue	174.1
Adipose tissue	tissue	161.3	medium
Esophagus	tissue	126.6	not detected
Postcentral gyrus	tissue	110.6
Thalamus	tissue	102.0
Midbrain	tissue	96.7
Caudate putamen	tissue	91.9
Cerebral cortex	tissue	85.6	high
Somatosensory cortex	tissue	85.6
Hippocampus	tissue	84.9	medium
Spinal cord	tissue	81.5
Superior colliculi	tissue	78.5
Pons	tissue	77.5
Motor cortex	tissue	76.1
Cerebellum	tissue	75.7	low
Colon	tissue	74.9	high
Heart muscle	tissue	74.5	not detected
Prefrontal cortex	tissue	74.2
Hippocampal formation	tissue	74.2
Entorhinal cortex	tissue	74.2
Temporal cortex	tissue	72.8
Occipital cortex	tissue	70.5
Insular cortex	tissue	68.6
Lung	tissue	67.2	medium
Nucleus accumbens	tissue	67.1
Medulla oblongata	tissue	66.0
Amygdala	tissue	64.5
Retrosplenial and cingulate cortex	tissue	63.6
Substantia nigra	tissue	63.4
Periaqueductal gray	tissue	63.1
Salivary gland	tissue	62.9	low
Liver	tissue	62.1	medium
Retrosplenial cortex	tissue	60.4
Skeletal muscle	tissue	59.2	not detected
Tongue	tissue	58.2
Rectum	tissue	55.0	medium
Corpus callosum	tissue	55.0
Hypothalamus	tissue	52.4
Small intestine	tissue	46.0	high
Olfactory bulb	tissue	41.9
Ventral forebrain	tissue	41.4
Gallbladder	tissue	41.3	medium
Septum	tissue	41.0
Spleen	tissue	40.5	low
Placenta	tissue	38.0	low
Basal ganglia	tissue	37.8	medium
Vagina	tissue	36.7	not detected
Stomach 1	tissue	34.5	medium
Locus coeruleus	tissue	34.1
Putamen	tissue	33.1
Duodenum	tissue	33.1	medium
Kidney	tissue	31.3	medium
Fallopian tube	tissue	29.4	low
Urinary bladder	tissue	27.8	low
Smooth muscle	tissue	25.7	not detected
Seminal vesicle	tissue	25.4	not detected
Cervix	tissue	24.7	medium
Breast	tissue	22.7	medium
Appendix	tissue	20.6	low
Prostate	tissue	19.7	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Centromedial thalamic nucleus (129.3), Inferior parietal lobule (126.5), Parieto-occipital transitional area (122.7), Posterior thalamic nucleus (119.5), Ventral posteromedial thalamic nucleus (118.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA, PRDM5

miRNA regulators (miRDB)

Targeting MGLL by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 100 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538

Functional genomics

gnomAD constraint: pLI 0.981, LOEUF 0.5, missense Z 1.16 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000265052 — one region, missense o/e 0.86.

Literature-anchored findings (GeneRIF, showing 40)

• not associated with susceptibility to alcoholism in a Japanese population. (PMID:17621164)
• full proteomic characterization of hMGL was carried out, which showed (1) an absence of intramolecular disulfide bridges in the functional, recombinant enzyme and (2) the post-translational removal of the enzyme’s N-terminal methionine (PMID:18452279)
• Identification of amino acids critical to the catalytic activity (PMID:18721756)
• Gene Ontology analysis indicated a significant alteration of oxygen transport (increased hemoglobin gene expression) and lipid metabolism [including monoglyceride lipase and low density lipoprotein receptor-related protein 5 (LRP5) gene]. (PMID:19233690)
• An apolar helix covering the active site also gives structural insight into the amphitropic character of MAGL, and likely explains how MAGL interacts with membranes to recruit its substrate. (PMID:19957260)
• MGL shares the classic fold of the alpha/beta hydrolase family but depicts an unusually large hydrophobic occluded tunnel with a highly flexible lid at its entry and the catalytic triad buried at its end. (PMID:19962385)
• Study shows that monoacylglycerol lipase (MAGL) is highly expressed in aggressive cancer cells and primary tumors; it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and tumor growth. (PMID:20079333)
• Identification of an active site hydrogen bond network in human monoacylglycerol lipase. (PMID:20464001)
• Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by serine hydrolase monoacylglycerol lipase (MAGL) in a transgenic mouse model with targeted disruption of MAGL. (PMID:20855465)
• One interval in the FAAH promoter and three intervals in the MGLL gene were associated with high BMI. (PMID:21118518)
• Data present a high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase. (PMID:21308848)
• High MAGL is associated with colorectal cancer. (PMID:21543155)
• MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and pharmacological or RNA-interference disruption of this enzyme impairs prostate cancer aggressiveness. (PMID:21802006)
• results suggest that MGL plays a negative regulatory role in phosphatidylinositol-3 kinase/Akt signaling and tumor cell growth (PMID:22349814)
• No association was found between our inflammatory bowel disease cohort and the candidate single nucleotide polymorphisms for MGL (CD/HC: P=0.37 and UC/HC: P=0.25). (PMID:22664939)
• MGL expression declines after peaking in infancy. (PMID:22827915)
• Data indicate that N,N-dimethyl-5-(4-phenoxyphenyl)-2H-tetrazole-2-carboxamide inhibited monoacylglycerol lipase (MAGL) with IC50 0.028 muM. (PMID:23455058)
• MGL interaction with a phospholipid membrane bilayer induces regional changes in the enzyme’s conformation that favor its recruiting lipophilic substrate from membrane stores to the active site resulting in enhanced MGL catalytic activity. (PMID:23553709)
• Mutation of Cys242 was also found to impair inhibition of monoacylglycerol lipase. (PMID:24368842)
• In obese humans, FAAH or MGL activity in adipocytes is not affected by diabetes, dyslipidaemia or other markers of metabolic dysfunction. (PMID:24593280)
• In subcutaneous adipose tissue, DAGL-a mRNA was upregulated and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) mRNAs were down-regulated in obese subjects, but the diets had no influence. (PMID:24616451)
• role of monoacylglycerol lipase (MAGL) in the cancer progress (PMID:24633487)
• Molecular dynamics and nudged elastic band simulations were used to explore the conformational transition pathway of the helix alpha4 of human monoacylglycerol lipase. (PMID:25078047)
• Our findings establish that MAGL promotes metastases in nasopharyngeal carcinoma (PMID:25120746)
• The study identified monoacylglycerol lipase as a YAP transcriptional target and an inhibitor of anchorage-dependent cell growth. (PMID:25636199)
• Monoacylglycerol lipase sulfenylation might act as an intrinsic neuroprotective mechanism by potentiating 2-AG signaling at CB1 receptors. (PMID:26000748)
• The data highlight specific inter-residue interactions within hMGL (PMID:26555264)
• there was evidence that MGLL rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the endocannabinoid system and addiction (PMID:26595473)
• the presence and differential distribution of fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in relation to CB1 during the maturation of human oocytes, was investigated. (PMID:26948343)
• This study unravels a novel mechanism of SND1 function and identifies MGLL as a unique tumor suppressor for HCC. MGLL might function as a homeostatic regulator of Akt restraining its activation. (PMID:26997225)
• MGLL may have a role in progression of gastrointestinal stromal tumors (PMID:27366945)
• RNA interference, specific pharmacological inhibitor JZL-184 and gene knock-in of MAGL were utilized to investigate the effects of MAGL on hepatocellular carcinoma (HCC) cell proliferation, apoptosis, and invasion. MAGL played important roles in both proliferation and invasion of HCC cells. (PMID:27767105)
• the upregulation of MAGL in hepatocellular carcinoma cells promoted cell growth and invasiveness abilities, and mediated epithelial-mesenchymal transition (PMID:27884159)
• we clarify the key role of Phe159 and Ile179, two conserved residues within the lid domain, in regulating substrate specificity in MAGL. We conclude by proposing that other structurally related lipases may share this lid-domain-mediated mechanism for substrate specificity. (PMID:28088576)
• This review summarizes the basics of monoglyceride metabolism and provides an overview on the therapeutic potential of MGL. [Review] (PMID:28213089)
• Using a multimethod approach, the authors show that the dynamically relevant Trp-289 and Leu-232 residues serve as communication hubs within an allosteric protein network that controls signal propagation to the active site, and thus, regulates active-inactive interconversion of human MGL. (PMID:29379013)
• Study utilizing colorectal cancer patients tissue samples, mouse tumor cell lines and xenograft models identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy. (PMID:29968710)
• Low mRNA expression and activity of monoacylglycerol lipase in human SH-SY5Y neuroblastoma cells (PMID:30978461)
• overexpression of MAGL inhibits the proliferation of MHCC97H hepatocellular carcinoma cells in vivo, and its mechanism may be associated to the release of inflammatory factors from tumor-associated macrophages (PMID:31357777)
• Brain structural changes in cannabis dependence: association with MAGL. (PMID:31695165)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mgll	ENSDARG00000036820
mus_musculus	Mgll	ENSMUSG00000033174
rattus_norvegicus	Mgll	ENSRNOG00000014508

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1346042) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 24 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased physiological sensitivity to xenobiotic	2
hyperactivity	1
decreased locomotor activity	1
abnormal eating behavior	1
increased thermal nociceptive threshold	1
decreased chemically-elicited antinociception	1
abnormal glucose homeostasis	1
abnormal lipid homeostasis	1
increased mean platelet volume	1
decreased circulating triglyceride level	1
decreased circulating insulin level	1
increased insulin sensitivity	1
hypoalgesia	1
decreased circulating glycerol level	1
decreased circulating ketone body level	1
decreased fatty acids level	1
increased oxygen consumption	1
improved glucose tolerance	1
hyporesponsive to tactile stimuli	1
increased body temperature	1
abnormal lipolysis	1
impaired lipolysis	1
decreased liver triglyceride level	1
impaired behavioral response to xenobiotic	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Mycolicibacterium smegmatis MC2 155	A0QNZ7	67.0%	Diamond
Mycobacterium tuberculosis H37Rv	O07427	67.0%	Diamond
Candida albicans SC5314	Q5ALW7	45.0%	Diamond
Bacillus subtilis subsp. subtilis str. 168	O34705	33.3%	Diamond
Monkeypox virus	A0A7H0DN16	100.0%	Diamond
Vaccinia virus WR	P18379	100.0%	Diamond
Vaccinia virus Copenhagen	P68465	100.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
KBTBD12	protein-coding	166348
ABTB1	protein-coding	80325
PODXL2	protein-coding	50512
SEC61A1	protein-coding	29927
MIR7976	ncRNA	102465857
TPRA1	protein-coding	131601
MCM2	protein-coding	4171

Protein

Protein identifiers

Monoglyceride lipase — Q99685 (reviewed: Q99685)

Alternative names: HU-K5, Lysophospholipase homolog, Lysophospholipase-like, Monoacylglycerol lipase

All UniProt accessions (6): A0A0C4DFN3, A0A3B3ITT3, C9JAM4, Q99685, H7C4E0, H7C5K5

UniProt curated annotations — full annotation on UniProt →

Function. Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain. Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol. Membrane.

Tissue specificity. Detected in adipose tissue, lung, liver, kidney, brain and heart.

Pathway. Glycerolipid metabolism; triacylglycerol degradation.

Miscellaneous. Short-term inhibition causes analgesia, while long-term inhibition causes tolerance to endocannabinoids acting on brain cannabinoid receptor CNR1, and a reduction in brain cannabinoid receptor CNR1 activity.

Similarity. Belongs to the AB hydrolase superfamily. Monoacylglycerol lipase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99685-1	1	yes
Q99685-2	2

RefSeq proteins (10): NP_001003794, NP_001243514, NP_001375241, NP_001375242, NP_001375243, NP_001375244, NP_001375245, NP_001375246, NP_001375247, NP_009214* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000073	AB_hydrolase_1	Domain
IPR022742	ABHD17C-like	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR051044	MAG_DAG_Lipase	Family

Pfam: PF12146

Enzyme classification (BRENDA)

• EC 3.1.1.23 — acylglycerol lipase (BRENDA: 16 organisms, 181 substrates, 293 inhibitors, 72 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

25 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-ARACHIDONOYLGLYCEROL	0.0097–0.122	12
4-METHYLUMBELLIFERYL BUTYRATE	0.084–0.162	11
MONOACYLGLYCEROL	0.15–0.3	8
2-OLEOYLGLYCEROL	—	7
2-(15-DEOXY-DELTA12,14-PROSTAGLANDIN J2)-GLYCERO	0.01–0.016	5
1-MONOOLEOYLGLYCEROL	0.083–0.51	3
LYSOPHOSPHATIDYLETHANOLAMINE	0.22–0.28	3
1(3)-MONOOLEOYLGLYCEROL	0.27	1
1-DECANOYL-RAC-GLYCEROL	0.02	1
1-MONOLAUROYLGLYCEROL	0.14	1
1-MONOMYRISTOYLGLYCEROL	0.12	1
2-MONOMYRISTOYLGLYCEROL	0.2	1
2-MONOOLEOYLGLYCEROL	0.059	1
4-NITROPHENYL ACETATE	0.2	1
7-HYDROXYCOUMARINYL ARACHIDONATE	0.0098	1

Catalyzed reactions (Rhea)

• 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + H2O = glycerol + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:26132)
• a 1-acylglycerol + H2O = glycerol + a fatty acid + H(+) (RHEA:34019)
• 1-octadecanoylglycerol + H2O = octadecanoate + glycerol + H(+) (RHEA:38363)
• 1-(9Z-octadecenoyl)-glycerol + H2O = glycerol + (9Z)-octadecenoate + H(+) (RHEA:38487)
• 2-(9Z-octadecenoyl)-glycerol + H2O = glycerol + (9Z)-octadecenoate + H(+) (RHEA:38491)
• 1-hexadecanoylglycerol + H2O = glycerol + hexadecanoate + H(+) (RHEA:39959)
• 2-hexadecanoylglycerol + H2O = glycerol + hexadecanoate + H(+) (RHEA:39963)
• 1-tetradecanoylglycerol + H2O = tetradecanoate + glycerol + H(+) (RHEA:44312)
• 1-dodecanoylglycerol + H2O = dodecanoate + glycerol + H(+) (RHEA:44316)
• 1-decanoylglycerol + H2O = decanoate + glycerol + H(+) (RHEA:44320)
• 1-octanoylglycerol + H2O = octanoate + glycerol + H(+) (RHEA:44328)
• a 2-acylglycerol + H2O = glycerol + a fatty acid + H(+) (RHEA:44688)

UniProt features (43 total): helix 16, strand 12, mutagenesis site 4, active site 3, turn 2, modified residue 2, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

30 structures by resolution:

PDB	Title	Method	Resolution (Å)
9F8D	Crystal structure of human monoacylglycerol lipase in complex with compound 7i	X-RAY DIFFRACTION	1.14
7ZPG	CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH LIGAND	X-RAY DIFFRACTION	1.16
3PE6	Crystal Structure of a soluble form of human MGLL in complex with an inhibitor	X-RAY DIFFRACTION	1.35
5ZUN	Crystal structure of human monoacylglycerol lipase in complex with compound 3l	X-RAY DIFFRACTION	1.35
9F8B	Crystal structure of human monoacylglycerol lipase in complex with compound 7n	X-RAY DIFFRACTION	1.4
9G4M	Crystal structure of monoacylglycerol lipase with BODIPY labeled probe	X-RAY DIFFRACTION	1.41
8RVF	CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE IN COMPLEX WITH COMPOUND 5	X-RAY DIFFRACTION	1.43
9FY5	CRYSTAL STRUCTURE OF HUMAN MONOACYLGLYCEROL LIPASE WITH COMPOUND	X-RAY DIFFRACTION	1.43
9I3Y	CRYSTAL STRUCTURE OF HUMAN MONOACYLGLYCEROL LIPASE WITH COMPOUND 17	X-RAY DIFFRACTION	1.45
9I5J	CRYSTAL STRUCTURE OF HUMAN MONOACYLGLYCEROL LIPASE WITH COMPOUND 27	X-RAY DIFFRACTION	1.48
9I56	CRYSTAL STRUCTURE OF HUMAN MONOACYLGLYCEROL LIPASE WITH COMPOUND 23	X-RAY DIFFRACTION	1.49
9I9C	CRYSTAL STRUCTURE OF HUMAN MONOACYLGLYCEROL LIPASE WITH COMPOUND 29	X-RAY DIFFRACTION	1.49
8PTC	COMPLEX CRYSTAL STRUCTURE OF MUTANT HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND 5d	X-RAY DIFFRACTION	1.51
9F8C	Crystal structure of human monoacylglycerol lipase in complex with compound 7m	X-RAY DIFFRACTION	1.52
9Q8D	CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH LIGAND	X-RAY DIFFRACTION	1.54
8AQF	CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND LEI-515	X-RAY DIFFRACTION	1.55
8PTQ	COMPLEX CRYSTAL STRUCTURE OF MUTANT HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND 5l	X-RAY DIFFRACTION	1.55
9F8A	Crystal structure of human monoacylglycerol lipase in complex with compound 7a	X-RAY DIFFRACTION	1.56
7PRM	CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND 13	X-RAY DIFFRACTION	1.65
8PTR	COMPLEX CRYSTAL STRUCTURE OF MUTANT HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND 5r	X-RAY DIFFRACTION	1.73
6BQ0	Structure of human monoacylglycerol lipase bound to a covalent inhibitor	X-RAY DIFFRACTION	2
3JW8	Crystal structure of human mono-glyceride lipase	X-RAY DIFFRACTION	2.1
3HJU	Crystal structure of human monoglyceride lipase	X-RAY DIFFRACTION	2.2
7L4T	Crystal structure of human monoacylglycerol lipase in complex with compound 1	X-RAY DIFFRACTION	2.2
7L4W	Crystal structure of human monoacylglycerol lipase in complex with compound 2d	X-RAY DIFFRACTION	2.2
7L4U	Crystal structure of human monoacylglycerol lipase in complex with compound 1h	X-RAY DIFFRACTION	2.25
6AX1	Structure of human monoacylglycerol lipase bound to a covalent inhibitor	X-RAY DIFFRACTION	2.26
7L50	Crystal structure of human monoacylglycerol lipase in complex with compound 4f	X-RAY DIFFRACTION	2.3
4UUQ	Crystal structure of human mono-glyceride lipase in complex with SAR127303	X-RAY DIFFRACTION	2.36
3JWE	Crystal structure of human mono-glyceride lipase in complex with SAR629	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99685-F1	94.36	0.86

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3)

Position	Role
122	nucleophile
239	charge relay system
269	charge relay system

Post-translational modifications (2)

Type	Positions
Phosphothreonine	10
3’-nitrotyrosine	58

Mutagenesis-validated functional residues (4)

Position	Phenotype
208	does not affect ability to hydrolyze 1- or 2-monoacylglycerol.
242	reduced 1-monoacylglycerol lipase activity.
194	does not affect ability to hydrolyze 1- or 2-monoacylglycerol.
201	does not affect ability to hydrolyze 1- or 2-monoacylglycerol.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 21; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

21 pathways:

ID	Pathway	Evidence
R-HSA-1482883	Acyl chain remodeling of DAG and TAG	curated
R-HSA-426048	Arachidonate production from DAG	curated
R-HSA-114508	Effects of PIP2 hydrolysis	—
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes	—
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	—
R-HSA-212165	Epigenetic regulation of gene expression	—
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	—
R-HSA-416476	G alpha (q) signalling events	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-1483206	Glycerophospholipid biosynthesis	—
R-HSA-109582	Hemostasis	—
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	electronic
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-1483257	Phospholipid metabolism	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—
R-HSA-163560	Triglyceride catabolism	electronic
R-HSA-8979227	Triglyceride metabolism	—

MSigDB gene sets: 395 (showing top): REACTOME_TRIGLYCERIDE_CATABOLISM, MODULE_52, HNF3ALPHA_Q6, LU_IL4_SIGNALING, GOBP_INFLAMMATORY_RESPONSE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, CMYB_01, MODULE_128, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, AP2_Q3, FOXO1_01, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, BEIER_GLIOMA_STEM_CELL_DN

GO Biological Process (14): lipid metabolic process (GO:0006629), fatty acid biosynthetic process (GO:0006633), inflammatory response (GO:0006954), regulation of signal transduction (GO:0009966), arachidonate metabolic process (GO:0019369), triglyceride catabolic process (GO:0019433), acylglycerol catabolic process (GO:0046464), regulation of inflammatory response (GO:0050727), regulation of sensory perception of pain (GO:0051930), monoacylglycerol catabolic process (GO:0052651), regulation of endocannabinoid signaling pathway (GO:2000124), fatty acid metabolic process (GO:0006631), lipid catabolic process (GO:0016042), regulation of retrograde trans-synaptic signaling by endocanabinoid (GO:0099178)

GO Molecular Function (6): phosphatidylcholine lysophospholipase A1 activity (GO:0004622), protein homodimerization activity (GO:0042803), monoacylglycerol lipase activity (GO:0047372), protein binding (GO:0005515), hydrolase activity (GO:0016787), carboxylic ester hydrolase activity (GO:0052689)

GO Cellular Component (11): endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), lipid droplet (GO:0005811), axon (GO:0030424), varicosity (GO:0043196), synapse (GO:0045202), parallel fiber to Purkinje cell synapse (GO:0098688), presynapse (GO:0098793), cerebellar climbing fiber to Purkinje cell synapse (GO:0150053)

Reactome top-level categories

16 top-level categories:

Category	Pathways
Metabolism of lipids	2
Glycerophospholipid biosynthesis	1
Triglyceride metabolism	1
Effects of PIP2 hydrolysis	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1
Phospholipid metabolism	1
Gene expression (Transcription)	1
Signal Transduction	1
Signaling by GPCR	1
GPCR downstream signalling	1
Metabolism	1
Hemostasis	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1

GO top-level categories

53 GO namespaces:

Category	Terms
cellular anatomical structure	4
acylglycerol catabolic process	2
lipid metabolic process	2
primary metabolic process	1
fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
defense response	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
long-chain fatty acid metabolic process	1
icosanoid metabolic process	1
unsaturated fatty acid metabolic process	1
olefinic compound metabolic process	1
triglyceride metabolic process	1
acylglycerol metabolic process	1
neutral lipid catabolic process	1
glycerolipid catabolic process	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
sensory perception of pain	1
regulation of sensory perception	1
monoacylglycerol metabolic process	1
regulation of G protein-coupled receptor signaling pathway	1
endocannabinoid signaling pathway	1
monocarboxylic acid metabolic process	1
catabolic process	1
retrograde trans-synaptic signaling by endocannabinoid	1
regulation of trans-synaptic signaling	1
lysophospholipase A1 activity	1
identical protein binding	1
protein dimerization activity	1
lipase activity	1
carboxylic ester hydrolase activity	1
binding	1
catalytic activity	1
hydrolase activity, acting on ester bonds	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
membrane	1
cell periphery	1
intracellular membraneless organelle	1
neuron projection	1
main axon	1
cell junction	1
excitatory synapse	1
synapse	1
asymmetric, glutamatergic, excitatory synapse	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
acylglycerol catabolic process	BP	direct assay
monoacylglycerol lipase activity	MF	direct assay
protein homodimerization activity	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,106 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MGLL	FAAH	O00519	970
MGLL	NCEH1	Q6PIU2	948
MGLL	CNR1	P21554	942
MGLL	LIPE	Q05469	919
MGLL	NAPEPLD	Q6IQ20	907
MGLL	DAGLA	Q9Y4D2	893
MGLL	ABHD6	Q9BV23	889
MGLL	DAGLB	Q8NCG7	809
MGLL	PNPLA2	Q96AD5	798
MGLL	ABHD12	Q8N2K0	792
MGLL	CES1	P23141	768
MGLL	GPR55	Q9Y2T6	758
MGLL	TRPV1	Q8NER1	722
MGLL	ABHD5	Q8WTS1	707
MGLL	LPL	P06858	683

IntAct

Human interaction partners of MGLL in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
HPCAL1	physical association	0.640	3
ADRB2	physical association	0.510	2
HTR4	physical association	0.370	1
LTB4R2	physical association	0.370	1
CHGB	physical association	0.000	1

BioGRID (45 interactions; top human partners by supporting records): C1orf111 (Affinity Capture-MS; 3 records), HPCAL1 (Affinity Capture-MS; 3 records), ADRB2 (Affinity Capture-Western; 2 records), USE1 (Affinity Capture-MS; 2 records), AQP6 (Two-hybrid), CD79A (Two-hybrid), CHGB (Two-hybrid), COQ9 (Two-hybrid), EBAG9 (Two-hybrid), FAM209A (Two-hybrid), FCER1G (Two-hybrid), GEM (Two-hybrid), GOLT1A (Two-hybrid), GPR152 (Two-hybrid), HIATL1 (Two-hybrid)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
SND1	“down-regulates quantity by destabilization”	MGLL	binding
MGLL	down-regulates	Proliferation

Disease & clinical

Genetic variants

Variant evidence for MGLL: 47 ClinVar records (0 pathogenic / likely pathogenic); 5 GWAS associations.

ClinVar

47 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	7
Benign	5

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 42 predictions of 1,159):

Position(s)	Effect	Δscore	Sites
3:127694974	donor_loss	1.0000
3:127710574–127710575	donor_loss	1.0000	5
3:127710666–127710667	acceptor_loss	1.0000	5
3:127781787–127781788	donor_loss	1.0000	5
3:127781896–127781897	acceptor_loss	1.0000	5
3:127821839–127821840	acceptor_loss	1.0000	6
3:127692324–127692325	acceptor_loss	0.9900	6
3:127694973–127694974	donor_loss	0.9900	2
3:127695191–127695192	acceptor_loss	0.9900	6
3:127710666	acceptor_loss	0.9900

AlphaMissense

747 missense substitutions predicted likely pathogenic (of 2,039 scored), across 203 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H269	8	0.988	0.996
D239	8	0.984	0.995
D76	8	0.982	0.993
D99	8	0.968	0.991
H49	8	0.956	0.992
H80	8	0.955	0.990
D197	8	0.951	0.982
H121	8	0.942	0.978
H54	8	0.913	0.987
S83	8	0.903	0.993
F209	8	0.895	0.972
H77	8	0.881	0.975
F73	8	0.879	0.989
H103	8	0.877	0.965
F93	8	0.860	0.976
H75	8	0.792	0.951
W289	7	0.965	0.991
F96	7	0.931	0.969
W35	7	0.926	0.970
M123	7	0.926	0.983

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000438

Disease associations

OMIM: gene MIM:609699 | disease phenotypes:

GWAS associations

5 associations:

Study	Trait	p-value
GCST010002_438	Refractive error	9e-21
GCST002337_53	Amyotrophic lateral sclerosis (sporadic)	6e-9
GCST012490_92	Femur bone mineral density x serum urate levels interaction	6e-9
GCST009179_4	Pars triangularis volume	3e-7
GCST010151_18	Carotid intima media thickness x smoking interaction	4e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0006527	smoking status measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4191 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the MGLL protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
ELCUBRAGISTAT	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 119,607 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

4 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL964	DISULFIRAM	4	39,061
CHEMBL3945728	ELCUBRAGISTAT	2	85
CHEMBL120563	THIRAM	2	80,036
CHEMBL184238	URB-597	1	425

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2-Acylglycerol ester turnover

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
LEI-515	Inhibition	9.3	pIC50
JJKK 048	Inhibition	9.3	pIC50
JNJ-42226314	Inhibition	8.95	pIC50
KML29	Inhibition	8.5	pIC50
JZL195	Inhibition	8.4	pIC50
MAGLi 432	Inhibition	8.38	pIC50
compound 4f [PMID: 34328319]	Inhibition	8.21	pIC50
JZL184	Inhibition	8.1	pIC50
MJN110	Inhibition	8.04	pIC50
ABX-1431	Irreversible inhibition	7.85	pIC50
compound 36 [PMID: 32429662]	Inhibition	7.82	pIC50
ABD-1970	Inhibition	7.74	pIC50
pristimerin	Inhibition	7.03	pIC50
irafamdastat	Inhibition	7.0	pIC50
CAY10499	Inhibition	6.84	pIC50
SA-57	Inhibition	5.85	pIC50

Binding affinities (BindingDB)

3350 measured of 4149 human assays (4539 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(S)-(2-Chloro-6-fluorophenyl)(3-(3,5-difluorophenyl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridin-6-yl)methanone	IC50	0.002 nM	US-11839663: Radiolabelled MGL pet ligands
2-[6-(3-tert-butylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.007 nM	US-11708359: Monoacylglycerol lipase modulators
2-[2-(3-tert-butylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.014 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[6-(4-tert-butylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.019 nM	US-11708359: Monoacylglycerol lipase modulators
2-[6-[3-(1-methylcyclopropyl)phenyl]-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.024 nM	US-11708359: Monoacylglycerol lipase modulators
2-[2-(5-tert-butyl-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.027 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
CHEMBL4749516	IC50	0.03 nM
CHEMBL5618354	IC50	0.03 nM
2-[6-[4-(1-methylcyclopropyl)phenyl]-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.034 nM	US-11708359: Monoacylglycerol lipase modulators
2-[3-[4-(trifluoromethyl)phenyl]-8-azaspiro[4.5]decane-8-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.039 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
CHEMBL4759880	IC50	0.04 nM
CHEMBL4785835	IC50	0.04 nM
CHEMBL5618586	IC50	0.04 nM
(2s,4S)-N-((1s,3S)-3-(4-Isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-	IC50	0.04 nM	US-11512059: Aminocyclobutanes as monoacylglycerol lipase modulators
2-[2-(3-propan-2-ylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.041 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.048 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
CHEMBL5575673	IC50	0.05 nM
CHEMBL5620312	IC50	0.06 nM
CHEMBL5618723	IC50	0.06 nM
CHEMBL5620200	IC50	0.06 nM
CHEMBL4745872	IC50	0.07 nM
2-[6-(3-chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.075 nM	US-11708359: Monoacylglycerol lipase modulators
CHEMBL5619084	IC50	0.08 nM
2-[2-(3-tert-butylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one	IC50	0.082 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[6-(3-tert-butylphenyl)-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.086 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.088 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[2-[3-(trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.094 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[2-(6-tert-butyl-2-pyridinyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.095 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[6-(3-tert-butylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.097 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
CHEMBL4756662	IC50	0.1 nM
CHEMBL4749293	IC50	0.1 nM
2-[(6S)-6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.1 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[3-(3-tert-butylphenyl)-8-azaspiro[4.5]decane-8-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.1 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[6-(4-propan-2-ylphenyl)-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.1 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
(7-((3,6-Dimethyl-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.5]nonan-2-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone	IC50	0.1 nM	US-11802111: Cyclobutyl amide monoacylglycerol lipase modulators
2-[2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.11 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[6-(4-tert-butylphenyl)-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.11 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[3-(4-tert-butylphenyl)-8-azaspiro[4.5]decane-8-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.11 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
(4-Fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5- trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9- epiminocycloocta[c]pyrazol-10-yl)methanone;	IC50	0.14 nM	US-11597728: Monoacylglycerol lipase modulators
CHEMBL4078217	IC50	0.16 nM
2-[6-(3-propan-2-ylphenyl)-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.17 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
(4-Bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl- 4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10- yl)methanone;	IC50	0.18 nM	US-11597728: Monoacylglycerol lipase modulators
(2s,4S)-N-((1s,3S)-3-(4-(tert-Butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-	IC50	0.2 nM	US-11512059: Aminocyclobutanes as monoacylglycerol lipase modulators
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone	IC50	0.2 nM	US-11608347: Octahydropyrido[1,2-alpha]pyrazines as MAGL inhibitors
(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- azaspiro[3.4]octan-6-one;	IC50	0.2 nM	US-11787798: Aryl piperidines as monoacylglycerol lipase modulators
2-[(3R,4R)-4-(4-tert-butylphenyl)-3-methylpiperidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.2 nM	US-11787798: Aryl piperidines as monoacylglycerol lipase modulators
(2s,4R*)-2-((2S*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine- 1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;	IC50	0.2 nM	US-11787798: Aryl piperidines as monoacylglycerol lipase modulators
((1s,3s)-3-Hydroxy-3-methylcyclobutyl)(7-(2-methyl-4-(trifluoromethyl)phenoxy)-2-azaspiro[3.5]nonan-2-yl)methanone	IC50	0.2 nM	US-11802111: Cyclobutyl amide monoacylglycerol lipase modulators
2-[6-(3-cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.21 nM	US-11505546: Azaspirocycles as monoacylglycerol lipase modulators
2-[6-(4-propan-2-ylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	IC50	0.21 nM	US-11708359: Monoacylglycerol lipase modulators

ChEMBL bioactivities

2378 potent at pChembl≥5 of 2523 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.85	IC50	0.014	nM	CHEMBL5785193
10.72	IC50	0.019	nM	CHEMBL5283351
10.68	IC50	0.021	nM	CHEMBL5569248
10.62	IC50	0.024	nM	CHEMBL5074982
10.57	IC50	0.027	nM	CHEMBL5832941
10.52	IC50	0.03	nM	CHEMBL4749516
10.52	IC50	0.03	nM	CHEMBL5618354
10.47	IC50	0.034	nM	CHEMBL5282368
10.41	IC50	0.039	nM	CHEMBL5892322
10.40	IC50	0.04	nM	CHEMBL4759880
10.40	IC50	0.04	nM	CHEMBL4785835
10.40	IC50	0.04	nM	CHEMBL5080928
10.40	IC50	0.04	nM	CHEMBL5618586
10.39	IC50	0.041	nM	CHEMBL5996643
10.32	IC50	0.048	nM	CHEMBL5793684
10.30	IC50	0.05	nM	CHEMBL5575673
10.30	IC50	0.05	nM	CHEMBL5569248
10.22	IC50	0.06	nM	CHEMBL5620312
10.22	IC50	0.06	nM	CHEMBL5618723
10.22	IC50	0.06	nM	CHEMBL5620200
10.15	IC50	0.07	nM	CHEMBL4745872
10.12	IC50	0.075	nM	CHEMBL5280083
10.10	IC50	0.08	nM	CHEMBL5619084
10.09	IC50	0.082	nM	CHEMBL5941658
10.07	IC50	0.086	nM	CHEMBL3787346
10.07	IC50	0.086	nM	CHEMBL5901923
10.06	IC50	0.088	nM	CHEMBL5747079
10.03	IC50	0.094	nM	CHEMBL6030416
10.02	IC50	0.095	nM	CHEMBL5751521
10.01	IC50	0.097	nM	CHEMBL5783701
10.00	IC50	0.1	nM	CHEMBL4756662
10.00	IC50	0.1	nM	CHEMBL4749293
10.00	IC50	0.1	nM	CHEMBL5992406
10.00	IC50	0.1	nM	CHEMBL5977282
10.00	IC50	0.1	nM	CHEMBL6025412
9.96	IC50	0.11	nM	CHEMBL5766234
9.96	IC50	0.11	nM	CHEMBL5809976
9.96	IC50	0.11	nM	CHEMBL6043445
9.85	IC50	0.14	nM	CHEMBL5989783
9.77	IC50	0.17	nM	CHEMBL6017690
9.74	IC50	0.18	nM	CHEMBL4097203
9.74	IC50	0.18	nM	CHEMBL4059676
9.74	IC50	0.18	nM	CHEMBL6067709
9.74	IC50	0.18	nM	CHEMBL5938868
9.70	IC50	0.2	nM	CHEMBL5089721
9.70	IC50	0.198	nM	CHEMBL3785379
9.70	IC50	0.2	nM	CHEMBL5766195
9.68	IC50	0.21	nM	CHEMBL5268216
9.68	IC50	0.21	nM	CHEMBL6029674
9.64	IC50	0.23	nM	CHEMBL5806570

PubChem BioAssay actives

1094 with measured affinity, of 2180 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4aR,8aS)-6-[3-[4-[2-(trifluoromethyl)phenyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one	1694504: Inhibition of MAGL (unknown origin) using 2-AG as substrate incubated for 15 mins followed by substrate addition and measured after 30 mins by mass spectrophotometry	ic50	<0.0001	uM
(4aR,8aS)-6-[3-[4-(2,4-dichlorophenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one	1694504: Inhibition of MAGL (unknown origin) using 2-AG as substrate incubated for 15 mins followed by substrate addition and measured after 30 mins by mass spectrophotometry	ic50	<0.0001	uM
(4aR,8aS)-6-[3-[4-[2-(trifluoromethoxy)phenyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one	1694504: Inhibition of MAGL (unknown origin) using 2-AG as substrate incubated for 15 mins followed by substrate addition and measured after 30 mins by mass spectrophotometry	ic50	<0.0001	uM
2-[6-[4-(1-methylcyclopropyl)phenyl]-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	1956446: Inhibition of MGL activity in human HeLa cells assessed as reduction in cleaved [1,3-3H glycerol] level using [glycerol-1,3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	<0.0001	uM
2-[6-(4-tert-butylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	1956446: Inhibition of MGL activity in human HeLa cells assessed as reduction in cleaved [1,3-3H glycerol] level using [glycerol-1,3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	<0.0001	uM
N-methyl-6-oxo-N-[3-(4-propan-2-ylphenyl)cyclobutyl]-7-oxa-5-azaspiro[3.4]octane-2-carboxamide	1813838: Inhibition of human MAGL expressed in HeLa cells using [glycerol-1, 3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	<0.0001	uM
2-[6-(3-tert-butylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	1815773: Inhibition of human MGL expressed in human HeLa cells assessed as amount of cleaved glycerol measured after 1 hrs by flow through assay	ic50	<0.0001	uM
2-[6-[3-(1-methylcyclopropyl)phenyl]-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	1815773: Inhibition of human MGL expressed in human HeLa cells assessed as amount of cleaved glycerol measured after 1 hrs by flow through assay	ic50	<0.0001	uM
(3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[1-(benzotriazole-1-carbonyl)piperidin-4-yl]-3-(4-fluorophenyl)azetidin-2-one	2099302: Inhibition of human MAGL	ic50	<0.0001	uM
[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone	2128392: Inhibition of human MAGL using 2-arachidonoylglycerol as substrate assessed as reduction in substrate hydrolysis by measuring arachidonic acid formation preincubated for 15 mins followed by substrate addition and measured after 30 mins by triple quadrupole mass spectrometric analysis	ic50	<0.0001	uM
[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone	2128392: Inhibition of human MAGL using 2-arachidonoylglycerol as substrate assessed as reduction in substrate hydrolysis by measuring arachidonic acid formation preincubated for 15 mins followed by substrate addition and measured after 30 mins by triple quadrupole mass spectrometric analysis	ic50	<0.0001	uM
(3S,4R)-4-(1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)-1-[1-(1,2,4-triazole-1-carbonyl)piperidin-4-yl]azetidin-2-one	2099302: Inhibition of human MAGL	ic50	0.0001	uM
(4aR,8aS)-6-[3-[4-(2,2-dimethylpropyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one	1694504: Inhibition of MAGL (unknown origin) using 2-AG as substrate incubated for 15 mins followed by substrate addition and measured after 30 mins by mass spectrophotometry	ic50	0.0001	uM
2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenyl]-3-chlorobenzonitrile	1694504: Inhibition of MAGL (unknown origin) using 2-AG as substrate incubated for 15 mins followed by substrate addition and measured after 30 mins by mass spectrophotometry	ic50	0.0001	uM
(4aR,8aS)-6-[4-[(R)-(4-methylphenyl)-phenylmethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one	1694504: Inhibition of MAGL (unknown origin) using 2-AG as substrate incubated for 15 mins followed by substrate addition and measured after 30 mins by mass spectrophotometry	ic50	0.0001	uM
2-[6-(3-chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	1956446: Inhibition of MGL activity in human HeLa cells assessed as reduction in cleaved [1,3-3H glycerol] level using [glycerol-1,3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	0.0001	uM
[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[4-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone	2128392: Inhibition of human MAGL using 2-arachidonoylglycerol as substrate assessed as reduction in substrate hydrolysis by measuring arachidonic acid formation preincubated for 15 mins followed by substrate addition and measured after 30 mins by triple quadrupole mass spectrometric analysis	ic50	0.0001	uM
[6-[(3-cyclopropyl-1H-pyrazol-5-yl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]methanone	2128392: Inhibition of human MAGL using 2-arachidonoylglycerol as substrate assessed as reduction in substrate hydrolysis by measuring arachidonic acid formation preincubated for 15 mins followed by substrate addition and measured after 30 mins by triple quadrupole mass spectrometric analysis	ic50	0.0001	uM
[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone	2128392: Inhibition of human MAGL using 2-arachidonoylglycerol as substrate assessed as reduction in substrate hydrolysis by measuring arachidonic acid formation preincubated for 15 mins followed by substrate addition and measured after 30 mins by triple quadrupole mass spectrometric analysis	ic50	0.0001	uM
[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone	2128392: Inhibition of human MAGL using 2-arachidonoylglycerol as substrate assessed as reduction in substrate hydrolysis by measuring arachidonic acid formation preincubated for 15 mins followed by substrate addition and measured after 30 mins by triple quadrupole mass spectrometric analysis	ic50	0.0001	uM
(3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[1-(benzotriazole-1-carbonyl)piperidin-4-yl]-3-(3-fluorophenyl)azetidin-2-one	2099302: Inhibition of human MAGL	ic50	0.0001	uM
(3R,4S)-4-(1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)-1-[1-(1,2,4-triazole-1-carbonyl)piperidin-4-yl]azetidin-2-one	2099302: Inhibition of human MAGL	ic50	0.0002	uM
1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-phenylpyrazol-3-yl)azetidine-1-carboxylate	1477446: Inhibition of human recombinant MAGL using 7-HCA as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence assay	ic50	0.0002	uM
1,1,1,3,3,3-hexafluoropropan-2-yl 3-[1-(3,4-difluorophenyl)pyrazol-3-yl]azetidine-1-carboxylate	1477446: Inhibition of human recombinant MAGL using 7-HCA as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence assay	ic50	0.0002	uM
2-[6-(4-propan-2-ylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	1956446: Inhibition of MGL activity in human HeLa cells assessed as reduction in cleaved [1,3-3H glycerol] level using [glycerol-1,3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	0.0002	uM
N-[3-(4-tert-butylphenyl)cyclobutyl]-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide	1813838: Inhibition of human MAGL expressed in HeLa cells using [glycerol-1, 3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	0.0002	uM
(3R,4S)-3,4-diphenyl-1-[1-(1,2,4-triazole-1-carbonyl)piperidin-4-yl]azetidin-2-one	2099302: Inhibition of human MAGL	ic50	0.0002	uM
1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1,5-diphenylpyrazol-3-yl)azetidine-1-carboxylate	1477446: Inhibition of human recombinant MAGL using 7-HCA as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence assay	ic50	0.0003	uM
2-[1-(4-cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one	1815773: Inhibition of human MGL expressed in human HeLa cells assessed as amount of cleaved glycerol measured after 1 hrs by flow through assay	ic50	0.0003	uM
N-[3-(4-cyclopropyl-3-methylphenyl)cyclobutyl]-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide	1813838: Inhibition of human MAGL expressed in HeLa cells using [glycerol-1, 3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	0.0003	uM
N-methyl-N-[3-[4-(1-methylcyclopropyl)phenyl]cyclobutyl]-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide	1813838: Inhibition of human MAGL expressed in HeLa cells using [glycerol-1, 3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	0.0003	uM
1-[(R)-[2-chloro-4-[(2S,3S)-4-(3-chlorophenyl)-2,3-dimethylpiperazine-1-carbonyl]phenyl]sulfinyl]-3,3-difluoropentan-2-one	2085900: Inhibition of human MAGL overexpressing HEK293T using 2-arachidonoylglycerol as substrate preincubated with compound for 20 mins followed by substrate addition and measured every 5 mins for 60 mins in presence of ATP by fluorescence based analysis	ic50	0.0003	uM
1,1,1,3,3,3-hexafluoropropan-2-yl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate	1477446: Inhibition of human recombinant MAGL using 7-HCA as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence assay	ic50	0.0004	uM
1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-benzylpyrazol-3-yl)azetidine-1-carboxylate	1477446: Inhibition of human recombinant MAGL using 7-HCA as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence assay	ic50	0.0004	uM
(4aR,8aS)-6-[3-[(4-chloro-2-phenoxyphenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one	1759752: Inhibition of recombinant MAGL (unknown origin) using 4-Nitrophenlyacetate as substrate incubated for 15 mins followed by substrate addition and measured after 5 mins	ic50	0.0004	uM
6-(4-benzhydrylpiperidine-1-carbonyl)-4H-1,4-benzoxazin-3-one	2255892: Inhibition of human MAGL using 4-nitrophenylacetate as substrate preincubated for 20 mins followed by substrate addition and measured after 5 mins by microplate reader assay	ic50	0.0004	uM
N-[3-(3-tert-butyl-4-fluorophenyl)cyclobutyl]-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide	1813838: Inhibition of human MAGL expressed in HeLa cells using [glycerol-1, 3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	0.0004	uM
[4-[bis(1,3-benzodioxol-5-yl)methyl]piperidin-1-yl]-(1,2,4-triazol-1-yl)methanone	1167641: Inhibition of human recombinant MAGL expressed in HEK293 cells using 2-AG as substrate	ic50	0.0004	uM
[4-[(3-phenoxyphenyl)methyl]piperazin-1-yl]-(1,2,4-triazol-1-yl)methanone	1167641: Inhibition of human recombinant MAGL expressed in HEK293 cells using 2-AG as substrate	ic50	0.0005	uM
1-[2-chloro-4-[(2S,3S)-4-(3-chlorophenyl)-2,3-dimethylpiperazine-1-carbonyl]phenyl]sulfinyl-3,3-difluoropentan-2-one	2085900: Inhibition of human MAGL overexpressing HEK293T using 2-arachidonoylglycerol as substrate preincubated with compound for 20 mins followed by substrate addition and measured every 5 mins for 60 mins in presence of ATP by fluorescence based analysis	ic50	0.0005	uM
N-[3-(3-cyclopropyl-5-methylphenyl)cyclobutyl]-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide	1813838: Inhibition of human MAGL expressed in HeLa cells using [glycerol-1, 3-3H]-oleoyl glycerol as substrate incubated for 1 hr	ic50	0.0005	uM
ethyl 2-[4-[3-methyl-4-(3-methylphenyl)piperazine-1-carbonyl]-2-nitrophenyl]sulfinylacetate	2085900: Inhibition of human MAGL overexpressing HEK293T using 2-arachidonoylglycerol as substrate preincubated with compound for 20 mins followed by substrate addition and measured every 5 mins for 60 mins in presence of ATP by fluorescence based analysis	ic50	0.0005	uM
4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenoxy]methyl]pyrrolidin-2-one	2005712: Inhibition of MAGL (unknown origin) using 2-arachidonoylglycerol as substrate preincubated with compound for 15 mins followed by substrate addition and measured after 30 mins by mass spectrometer analysis	ic50	0.0005	uM
(4-benzhydrylpiperazin-1-yl)-(benzotriazol-1-yl)methanone	693811: Inhibition of human MAGL assessed as [3H]-2-OG hydrolysis preincubated for 30 mins before [3H]-2-OG addition measured after 10 mins by liquid scintillation counting	ic50	0.0005	uM
1-[3-(2-chlorophenyl)phenyl]-4-[4-(1,3-thiazole-2-carbonyl)piperazin-1-yl]pyrrolidin-2-one	1387472: Inhibition of His-tagged human MAGL expressed in Escherichia coli BL21(DE3) assessed as reduction in arachidonic acid production from 2-arachidonoylglycerol pre-incubated for 60 mins by mass spectrometry	ic50	0.0006	uM
[4-[bis(1,3-benzodioxol-5-yl)methylidene]piperidin-1-yl]-(1,2,4-triazol-1-yl)methanone	1363896: Inhibition of human MAGL	ic50	0.0006	uM
6-[4-[bis(4-fluorophenyl)methyl]piperidine-1-carbonyl]-4H-1,4-benzoxazin-3-one	2255892: Inhibition of human MAGL using 4-nitrophenylacetate as substrate preincubated for 20 mins followed by substrate addition and measured after 5 mins by microplate reader assay	ic50	0.0006	uM
1-[2-chloro-4-[(2S,3S)-4-(4-chloro-2-pyridinyl)-2,3-dimethylpiperazine-1-carbonyl]phenyl]sulfinyl-3,3-difluoropentan-2-one	2085900: Inhibition of human MAGL overexpressing HEK293T using 2-arachidonoylglycerol as substrate preincubated with compound for 20 mins followed by substrate addition and measured every 5 mins for 60 mins in presence of ATP by fluorescence based analysis	ic50	0.0006	uM
[4-[bis(1,3-benzodioxol-5-yl)-hydroxymethyl]piperidin-1-yl]-(1,2,4-triazol-1-yl)methanone	1167641: Inhibition of human recombinant MAGL expressed in HEK293 cells using 2-AG as substrate	ic50	0.0007	uM
(4aR,8aS)-6-[3-[2-[2-bromo-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one	1759752: Inhibition of recombinant MAGL (unknown origin) using 4-Nitrophenlyacetate as substrate incubated for 15 mins followed by substrate addition and measured after 5 mins	ic50	0.0007	uM

CTD chemical–gene interactions

77 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases abundance, increases expression, decreases expression	4
bisphenol A	decreases expression, decreases methylation, increases expression	3
sodium arsenite	increases expression, affects methylation, decreases expression	3
(+)-JQ1 compound	affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	3
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	increases expression	2
Formaldehyde	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
Valproic Acid	increases methylation, decreases expression, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
TL8-506	affects cotreatment, increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sulforaphane	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	increases abundance, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric chloride	increases expression	1
nickel sulfate	increases expression	1
triadimefon	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1

ChEMBL screening assays

334 unique, capped per target: 329 binding, 3 admet, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1036883	Binding	Inhibition of human MGL activity using [3H]2-oleoylglycerol substrate at 10 nM measured upto 1 hr by high dilution reversibility assay	Bis(dialkylaminethiocarbonyl)disulfides as potent and selective monoglyceride lipase inhibitors. — *J Med Chem*
CHEMBL4201497	ADMET	Stability assessed as human MGL-mediated compound hydrolysis by HPLC analysis	( R)- N-(1-Methyl-2-hydroxyethyl)-13-( S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes. — *J Med Chem*
CHEMBL5304996	Functional	[3H] 2-OG cleavage activity assay (HeLa)	Data for DCP probe JNJ-42226314

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1TJ	Abcam U-87MG MGLL KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for MGLL across ~30M SureChEMBL compounds — explore on Sugi Predict.