2-Acylglycerol ester turnover | Enzymes | IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY

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Endocannabinoid turnover
2-Acylglycerol ester turnover

2-Acylglycerol ester turnover C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Enzymes

Targets of relevance to immunopharmacology are highlighted in blue

DAGLα (diacylglycerol lipase α) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1396

Nomenclature

diacylglycerol lipase α

Common abbreviation

DAGLα

Previous and unofficial names

diacylglycerol lipase | diacylglycerol lipase, alpha | FMP30 | Neural stem cell-derived dendrite regulator

Genes

DAGLA (Hs), Dagla (Mm), Dagla (Rn)

Ensembl ID

ENSG00000134780 (Hs), ENSMUSG00000035735 (Mm), ENSRNOG00000027264 (Rn)

UniProtKB AC

Q9Y4D2 (Hs), Q6WQJ1 (Mm), Q5YLM1 (Rn)

EC number

3.1.1.-

Endogenous substrates

diacylglycerol

Inhibitors

LEI105 pIC₅₀ 8.5 [3]

DO34 pIC₅₀ 8.2 [13]

DH376 pIC₅₀ 8.2 [13]

KT-109 pIC₅₀ 5.6 [7]

DAGLβ (diacylglycerol lipase β) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1397

Nomenclature

diacylglycerol lipase β

Common abbreviation

DAGLβ

Previous and unofficial names

diacylglycerol lipase | diacylglycerol lipase, beta | KCCR13L | neural stem cell-derived dendrite regulator | NSDDR

Genes

DAGLB (Hs), Daglb (Mm), Daglb (Rn)

Ensembl ID

ENSG00000164535 (Hs), ENSMUSG00000039206 (Mm), ENSRNOG00000001079 (Rn)

UniProtKB AC

Q8NCG7 (Hs), Q91WC9 (Mm), P0C1S9 (Rn)

EC number

3.1.1.-

Endogenous substrates

diacylglycerol

Inhibitors

DH376 pIC₅₀ 8.6 [13]

DO34 pIC₅₀ 8.1 [13]

LEI105 pIC₅₀ 8.1 [3]

KT-109 pIC₅₀ 7.1 [7]

MAGL (monoacylglycerol lipase) C Show summary »« Hide summary More detailed page go icon to follow link

ABHD2 (αβ-Hydrolase 2) Show summary »« Hide summary

Target Id

3147

Nomenclature

αβ-Hydrolase 2

Common abbreviation

ABHD2

Previous and unofficial names

abhydrolase domain containing 2, acylglycerol lipase | abhydrolase domain containing 2 | monoacylglycerol lipase ABHD2 | 2-arachidonoylglycerol hydrolase

Genes

ABHD2 (Hs), Abhd2 (Mm), Abhd2 (Rn)

Ensembl ID

ENSG00000140526 (Hs), ENSMUSG00000039202 (Mm), ENSRNOG00000017120 (Rn)

UniProtKB AC

P08910 (Hs), Q9QXM0 (Mm)

EC number

3.1.1.23

Comment

ABHD2 is an acylglycerol lipase of the endocannabinoid system. In human spermatozoa ABHD2 activity (depletion of 2-arachidonoylglycerol in the sperm membrane) results in calcium influx via the calcium channel CatSper1, which leads to sperm activation [10].

ABHD6 (αβ-Hydrolase 6) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2919

Nomenclature

αβ-Hydrolase 6

Common abbreviation

ABHD6

Previous and unofficial names

2-arachidonoylglycerol hydrolase | abhydrolase domain-containing protein 6 | alpha/beta-Hydrolase domain containing 6 | abhydrolase domain containing 6 | abhydrolase domain containing 6, acylglycerol lipase

Genes

ABHD6 (Hs), Abhd6 (Mm), Abhd6 (Rn)

Ensembl ID

ENSG00000163686 (Hs), ENSMUSG00000025277 (Mm), ENSRNOG00000008167 (Rn)

UniProtKB AC

Q9BV23 (Hs), Q8R2Y0 (Mm), Q5XI64 (Rn)

EC number

3.1.1.23

Endogenous substrates

1-arachidonoylglycerol > 2-arachidonoylglycerol > 1-oleoylglycerol > 2-oleoyl glycerol [11]

Selective inhibitors

WWL70 pIC₅₀ 7.2 [8]

WWL123 pIC₅₀ 6.4 [2]

Comment

ABHD6 has also been shown to accept diacylglycerol as a substrate, thereby producing 2-acylglycerols [16]. WWL70 has been suggested to have activity at oxidative metabolic pathways independent of ABHD6 [15].

ABHD12 (αβ-Hydrolase 12) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3070

Nomenclature

αβ-Hydrolase 12

Common abbreviation

ABHD12

Previous and unofficial names

abhydrolase domain containing 12 | abhydrolase domain containing 12, lysophospholipase | BEM46L2 | Monoacylglycerol lipase ABHD12

Genes

ABHD12 (Hs), Abhd12 (Mm), Abhd12 (Rn)

Ensembl ID

ENSG00000100997 (Hs), ENSMUSG00000032046 (Mm), ENSRNOG00000036934 (Rn)

UniProtKB AC

Q8N2K0 (Hs), Q99LR1 (Mm), Q6AYT7 (Rn)

EC number

3.1.1.23

Selective inhibitors

DO264 pIC₅₀ 8.0 [14]

References

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1. Aaltonen N, Savinainen JR, Ribas CR, Rönkkö J, Kuusisto A, Korhonen J, Navia-Paldanius D, Häyrinen J, Takabe P, Käsnänen H et al.. (2013) Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase. Chem Biol, 20 (3): 379-90. [PMID:23521796]

2. Bachovchin DA, Ji T, Li W, Simon GM, Blankman JL, Adibekian A, Hoover H, Niessen S, Cravatt BF. (2010) Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening. Proc Natl Acad Sci USA, 107 (49): 20941-6. [PMID:21084632]

3. Baggelaar MP, Chameau PJ, Kantae V, Hummel J, Hsu KL, Janssen F, van der Wel T, Soethoudt M, Deng H, den Dulk H et al.. (2015) Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons. J Am Chem Soc, 137 (27): 8851-7. [PMID:26083464]

4. Chang JW, Niphakis MJ, Lum KM, Cognetta 3rd AB, Wang C, Matthews ML, Niessen S, Buczynski MW, Parsons LH, Cravatt BF. (2012) Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates. Chem Biol, 19 (5): 579-88. [PMID:22542104]

5. Ghafouri N, Tiger G, Razdan RK, Mahadevan A, Pertwee RG, Martin BR, Fowler CJ. (2004) Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol. Br J Pharmacol, 143 (6): 774-84. [PMID:15492019]

6. Granchi C, Rizzolio F, Bordoni V, Caligiuri I, Manera C, Macchia M, Minutolo F, Martinelli A, Giordano A, Tuccinardi T. (2016) 4-Aryliden-2-methyloxazol-5(4H)-one as a new scaffold for selective reversible MAGL inhibitors. J Enzyme Inhib Med Chem, 31 (1): 137-46. [PMID:25669350]

7. Hsu KL, Tsuboi K, Adibekian A, Pugh H, Masuda K, Cravatt BF. (2012) DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses. Nat Chem Biol, 8 (12): 999-1007. [PMID:23103940]

8. Li W, Blankman JL, Cravatt BF. (2007) A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases. J Am Chem Soc, 129 (31): 9594-5. [PMID:17629278]

9. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH et al.. (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol, 5 (1): 37-44. [PMID:19029917]

10. Miller MR, Mannowetz N, Iavarone AT, Safavi R, Gracheva EO, Smith JF, Hill RZ, Bautista DM, Kirichok Y, Lishko PV. (2016) Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. Science, 352 (6285): 555-9. [PMID:26989199]

11. Navia-Paldanius D, Savinainen JR, Laitinen JT. (2012) Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12). J Lipid Res, 53 (11): 2413-24. [PMID:22969151]

12. Niphakis MJ, Cognetta 3rd AB, Chang JW, Buczynski MW, Parsons LH, Byrne F, Burston JJ, Chapman V, Cravatt BF. (2013) Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. ACS Chem Neurosci, 4 (9): 1322-32. [PMID:23731016]

13. Ogasawara D, Deng H, Viader A, Baggelaar MP, Breman A, den Dulk H, van den Nieuwendijk AM, van den Nieuwendijk AM, Soethoudt M, van der Wel T et al.. (2016) Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proc Natl Acad Sci USA, 113 (1): 26-33. [PMID:26668358]

14. Ogasawara D, Ichu TA, Jing H, Hulce JJ, Reed A, Ulanovskaya OA, Cravatt BF. (2019) Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase α/β-Hydrolase Domain-Containing 12 (ABHD12). J Med Chem, 62 (3): 1643-1656. [PMID:30720278]

15. Tanaka M, Moran S, Wen J, Affram K, Chen T, Symes AJ, Zhang Y. (2017) WWL70 attenuates PGE2 production derived from 2-arachidonoylglycerol in microglia by ABHD6-independent mechanism. J Neuroinflammation, 14 (1): 7. [PMID:28086912]

16. van Esbroeck ACM, Kantae V, Di X, van der Wel T, den Dulk H, Stevens AF, Singh S, Bakker AT, Florea BI, Stella N et al.. (2019) Identification of α,β-Hydrolase Domain Containing Protein 6 as a Diacylglycerol Lipase in Neuro-2a Cells. Front Mol Neurosci, 12: 286. [PMID:31849602]

17. Wyatt RM, Fraser I, Welty N, Lord B, Wennerholm M, Sutton S, Ameriks MK, Dugovic C, Yun S, White A et al.. (2020) Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor. J Pharmacol Exp Ther, 372 (3): 339-353. [PMID:31818916]

NC-IUPHAR subcommittee and family contributors

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Stephen P.H. Alexander
Associate Professor in Molecular Pharmacology
Life Sciences E Floor
University of Nottingham Medical School
Nottingham NG7 2UH
UK

Patrick Doherty
Wolfson Centre for Age-Related Diseases
Kings College London
Wolfson Wing, Hodgkin Building
Guys Campus
London
SE1 1UL
UK

Christopher J. Fowler
Building 6B, 2nd floor, University Hospital of Umeå
SE-90187 Umeå
Sweden

Jürg Gertsch
Institute of Biochemistry and Molecular Medicine
University of Bern
Bühlstrasse 28, CH-3012 Bern
Switzerland

Mario van der Stelt
Department of Molecular Physiology
Leiden Institute of Chemistry
Leiden University
2333 CC Leiden
The Netherlands

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Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.