αβ-Hydrolase 12 | 2-Acylglycerol ester turnover | IUPHAR/BPS Guide to PHARMACOLOGY

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αβ-Hydrolase 12

target has curated data in GtoImmuPdb

Target id: 3070

Nomenclature: αβ-Hydrolase 12

Family: 2-Acylglycerol ester turnover

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 398 20p11.21 ABHD12 abhydrolase domain containing 12
Mouse 1 398 Chromosome 2, 74.74 cM Abhd12 abhydrolase domain containing 12
Rat 1 398 3q41 Abhd12 abhydrolase domain containing 12
Gene and Protein Information Comments
Alternatively spliced transcript variants encoding different protein isoforms have been noted for hABHD12. The shorter isoform a (398 aa) is the predominantly expressed isoform. Isoform b is 404 aa and has a distinct C-terminus compared to isoform a. In the mouse isoform 1 is the longest at 398 aa.
Previous and Unofficial Names
BEM46L2 | Monoacylglycerol lipase ABHD12
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.1.1.23

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
DO264 Hs Inhibition 8.0 pIC50 7
pIC50 8.0 (IC50 1.1x10-8 M) [7]
orlistat Hs Inhibition 7.1 pIC50 5
pIC50 7.1 (IC50 8x10-8 M) [5]
Description: Inhibition of recombinant ABHD12 expressed in HEK293T cells, by SDS-PAGE using rhodamine-tagged FP probe.
Immunopharmacology Comments
The lysophosphatidylserine (lyso-PSs) and lysophosphatidylinositol (lyso-PI) class lipide are immunomodulators that regulate immunological and neurological processes. ABHD12 is one of a number of lyso-PS lipases that are implicated in lyso-PS-induced cytokine production. Pharmacological inhibition of ABHD12 augments inflammatory cytokine production in human macrophages, which suggests a role for this enzyme in (lyso)-PS/PI metabolism and signalling, and downstream immunological functions [7-8]. Through its ability (albeit poorly) to hydrolyse the endocannabinoid 2-arachidonoylglycerol (2-AG) it is proposed as a participant in the control of cannabinoid CB1 receptor signalling in the brain [9]. However, whether ABHD12 is a genuine and functional member to the endocannabinoid system remains to be established.
Immuno Process Associations
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0050727 regulation of inflammatory response IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0050727 regulation of inflammatory response IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC)
Description: PHARC is caused by homozygous or compound heterozygous mutation in the ABHD12 gene
OMIM: 612674
References:  1,3-4,6,10
General Comments
ABHD12 inactivates the endocannibinoid 2-arachidonoyl glycerol (2-AG) by converting it into the metabolites arachidonate and glycerol [2-3,9].

References

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1. Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF. (2013) ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC. Proc. Natl. Acad. Sci. U.S.A., 110 (4): 1500-5. [PMID:23297193]

2. Blankman JL, Simon GM, Cravatt BF. (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol., 14 (12): 1347-56. [PMID:18096503]

3. Fiskerstrand T, H'mida-Ben Brahim D, Johansson S, M'zahem A, Haukanes BI, Drouot N, Zimmermann J, Cole AJ, Vedeler C, Bredrup C et al.. (2010) Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism. Am. J. Hum. Genet., 87 (3): 410-7. [PMID:20797687]

4. Fiskerstrand T, Knappskog P, Majewski J, Wanders RJ, Boman H, Bindoff LA. (2009) A novel Refsum-like disorder that maps to chromosome 20. Neurology, 72 (1): 20-7. [PMID:19005174]

5. Hoover HS, Blankman JL, Niessen S, Cravatt BF. (2008) Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg. Med. Chem. Lett., 18 (22): 5838-41. [PMID:18657971]

6. Nishiguchi KM, Avila-Fernandez A, van Huet RA, Corton M, Pérez-Carro R, Martín-Garrido E, López-Molina MI, Blanco-Kelly F, Hoefsloot LH, van Zelst-Stams WA et al.. (2014) Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration. Ophthalmology, 121 (8): 1620-7. [PMID:24697911]

7. 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]

8. Ogasawara D, Ichu TA, Vartabedian VF, Benthuysen J, Jing H, Reed A, Ulanovskaya OA, Hulce JJ, Roberts A, Brown S et al.. (2018) Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nat. Chem. Biol., 14 (12): 1099-1108. [PMID:30420694]

9. Savinainen JR, Saario SM, Laitinen JT. (2012) The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiol (Oxf), 204 (2): 267-76. [PMID:21418147]

10. Tingaud-Sequeira A, Raldúa D, Lavie J, Mathieu G, Bordier M, Knoll-Gellida A, Rambeau P, Coupry I, André M, Malm E et al.. (2017) Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC. Neurobiol. Dis., 98: 36-51. [PMID:27890673]

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