Navia-Paldanius_2012_J.Lipid.Res_53_2413

Reference

Title : Biochemical and pharmacological characterization of human alpha\/beta-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12) - Navia-Paldanius_2012_J.Lipid.Res_53_2413
Author(s) : Navia-Paldanius D , Savinainen JR , Laitinen JT
Ref : J Lipid Res , 53 :2413 , 2012
Abstract :

In the central nervous system, three enzymes belonging to the serine hydrolase family are thought to regulate the life time of the endocannabinoid 2-arachidonoylglycerol (C20:4) (2-AG). From these, monoacylglycerol lipase (MAGL) is well characterized and, on a quantitative basis, is the main 2-AG hydrolase. The postgenomic proteins alpha/beta-hydrolase domain containing (ABHD)6 and ABHD12 remain poorly characterized. By applying a sensitive fluorescent glycerol assay, we delineate the substrate preferences of human ABHD6 and ABHD12 in comparison with MAGL. We show that the three hydrolases are genuine MAG lipases; medium-chain saturated MAGs were the best substrates for hABHD6 and hMAGL, whereas hABHD12 preferred the 1 (3)- and 2-isomers of arachidonoylglycerol. Site-directed mutagenesis of the amino acid residues forming the postulated catalytic triad (ABHD6: S148-D278-H306, ABHD12: S246-D333-H372) abolished enzymatic activity as well as labeling with the active site serine-directed fluorophosphonate probe TAMRA-FP. However, the role of D278 and H306 as residues of the catalytic core of ABHD6 could not be verified because none of the mutants showed detectable expression. Inhibitor profiling revealed striking potency differences between hABHD6 and hABHD12, a finding that, when combined with the substrate profiling data, should facilitate further efforts toward the design of potent and selective inhibitors, especially those targeting hABHD12, which currently lacks such inhibitors.

PubMedSearch : Navia-Paldanius_2012_J.Lipid.Res_53_2413
PubMedID: 22969151
Gene_locus related to this paper: human-ABHD6 , human-ABHD12

Related information

Inhibitor FP-TAMRA
Gene_locus human-ABHD6    human-ABHD12

Citations formats

Navia-Paldanius D, Savinainen JR, Laitinen JT (2012)
Biochemical and pharmacological characterization of human alpha\/beta-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)
J Lipid Res 53 :2413

Navia-Paldanius D, Savinainen JR, Laitinen JT (2012)
J Lipid Res 53 :2413