αβ-Hydrolase 12
Target id: 3070
Nomenclature: αβ-Hydrolase 12
Abbreviated Name: ABHD12
Family: 2-Acylglycerol ester turnover
Contents:
Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 1 | 398 | 20p11.21 | ABHD12 | abhydrolase domain containing 12, lysophospholipase | |
| Mouse | 1 | 398 | 2 G3 | Abhd12 | abhydrolase domain containing 12 | |
| Rat | 1 | 398 | 3q41 | Abhd12 | abhydrolase domain containing 12, lysophospholipase | |
| 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 | abhydrolase domain containing 12, lysophospholipase | BEM46L2 | Monoacylglycerol lipase ABHD12 |
| Database Links |
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| Alphafold | Q8N2K0 (Hs), Q99LR1 (Mm), Q6AYT7 (Rn) |
| BRENDA | 3.1.1.23 |
| ChEMBL Target | CHEMBL5516 (Hs), CHEMBL5972 (Mm), CHEMBL3708071 (Rn) |
| Ensembl Gene | ENSG00000100997 (Hs), ENSMUSG00000032046 (Mm), ENSRNOG00000036934 (Rn) |
| Entrez Gene | 26090 (Hs), 76192 (Mm), 499913 (Rn) |
| Human Protein Atlas | ENSG00000100997 (Hs) |
| KEGG Enzyme | 3.1.1.23 |
| KEGG Gene | hsa:26090 (Hs), mmu:76192 (Mm), rno:499913 (Rn) |
| OMIM | 613599 (Hs) |
| Pharos | Q8N2K0 (Hs) |
| RefSeq Nucleotide | NM_001042472 (Hs), NM_024465 (Mm), NM_001024314 (Rn) |
| RefSeq Protein | NP_001035937 (Hs), NP_077785 (Mm), NP_001019485 (Rn) |
| UniProtKB | Q8N2K0 (Hs), Q99LR1 (Mm), Q6AYT7 (Rn) |
| Wikipedia | ABHD12 (Hs) |
| Enzyme Reaction |
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Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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 [9-10]. 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 [11]. However, whether ABHD12 is a genuine and functional member to the endocannabinoid system remains to be established. |
| Clinically-Relevant Mutations and Pathophysiology
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| General Comments |
| ABHD12 is a 398-aa protein, with serine hydrolase activity. It has a molecular weight of ~45 kDa. A single TM is predicted at 75-95, with an extracellular catalytic domain. ABHD12 is a monoacylglycerol hydrolase [7], but may also regulate lysophosphatidylserine levels [6]. ABHD12 inactivates the endocannibinoid 2-arachidonoyl glycerol (2-AG) by converting it into the metabolites arachidonate and glycerol [2-3,11]. |
References
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 USA, 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. Kamat SS, Camara K, Parsons WH, Chen DH, Dix MM, Bird TD, Howell AR, Cravatt BF. (2015) Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay. Nat Chem Biol, 11 (2): 164-71. [PMID:25580854]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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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