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 [11], but may also regulate lysophosphatidylserine levels [8]. Loss-of-function mutations in ABHD12 are associated with a disorder known as PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) [5].

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. U.S.A., 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. 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]

6. 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]

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. 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]

9. 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]

10. 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]

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. U.S.A., 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. 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]

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