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, lysophospholipase
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
abhydrolase domain containing 12 | BEM46L2 | Monoacylglycerol lipase ABHD12
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
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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