Family Report for: Epoxide-hydrolase_like

This family closely related to Abhydrolase_6 contains previously separated families (in Pfam they are partially included in Abhydrolase_6). In epoxide hydrolase, haloalkane dehalogenase, haloacetate_dehalogenase, the catalytic triad nucleophile is an invariable aspartate. Asp attacks a carbon of the epoxide moiety, opening the ring and forming an ester-linked substrate-enzyme intermediate complex. An activated water molecule, hydrolyzes the ester bond and releases diol as the product of catalysis. Two Tyr residues are located on the opposite side of the active site from the nucleophile. They hydrogen bond with the epoxide oxygen, positioning the substrate in the active site for nucleophilic attack. In Cif one of the Tyr is replaced by His

Title: alpha/beta-Hydrolase Domain-Containing 6 (ABHD6)- A Multifunctional Lipid Hydrolase
Pusch LM, Riegler-Berket L, Oberer M, Zimmermann R, Taschler U
Ref: Metabolites, 12:, 2022 : PubMed
Abstract


ESTHER: Pusch_2022_Metabolites_12_761
PubMedSearch: Pusch 2022 Metabolites 12 761
PubMedID: 36005632
Gene_locus related to this paper: human-ABHD6

Abstract

alpha/beta-hydrolase domain-containing 6 (ABHD6) belongs to the alpha/beta-hydrolase fold superfamily and was originally discovered in a functional proteomic approach designed to discover monoacylglycerol (MAG) hydrolases in the mouse brain degrading the endocannabinoid 2-arachidonoylglycerol. Subsequent studies confirmed that ABHD6 acts as an MAG hydrolase regulating cannabinoid receptor-dependent and -independent signaling processes. The enzyme was identified as a negative modulator of insulin secretion and regulator of energy metabolism affecting the pathogenesis of obesity and metabolic syndrome. It has been implicated in the metabolism of the lysosomal co-factor bis(monoacylglycerol)phosphate and in the surface delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. Finally, ABHD6 was shown to affect cancer cell lipid metabolism and tumor malignancy. Here, we provide new insights into the experimentally derived crystal structure of ABHD6 and its possible orientation in biological membranes, and discuss ABHD6's functions in health and disease.



        

Title: Epoxide hydrolases: structure, function, mechanism, and assay
Arand M, Cronin A, Adamska M, Oesch F
Ref: Methods Enzymol, 400:569, 2005 : PubMed
Abstract


ESTHER: Arand_2005_Methods.Enzymol_400_569
PubMedSearch: Arand 2005 Methods.Enzymol 400 569
PubMedID: 16399371

Abstract

Epoxide hydrolases are a class of enzymes important in the detoxification of genotoxic compounds, as well as in the control of physiological signaling molecules. This chapter gives an overview on the function, structure, and enzymatic mechanism of structurally characterized epoxide hydrolases and describes selected assays for the quantification of epoxide hydrolase activity.



        

Title: The telltale structures of epoxide hydrolases
Arand M, Cronin A, Oesch F, Mowbray SL, Jones TA
Ref: Drug Metabolism Reviews, 35:365, 2003 : PubMed
Abstract


ESTHER: Arand_2003_Drug.Metab.Rev_35_365
PubMedSearch: Arand 2003 Drug.Metab.Rev 35 365
PubMedID: 14705866

Abstract

Traditionally, epoxide hydrolases (EH) have been regarded as xenobiotic-metabolizing enzymes implicated in the detoxification of foreign compounds. They are known to play a key role in the control of potentially genotoxic epoxides that arise during metabolism of many lipophilic compounds. Although this is apparently the main function for the mammalian microsomal epoxide hydrolase (mEH), evidence is now accumulating that the mammalian soluble epoxide hydrolase (sEH), despite its proven role in xenobiotic metabolism, also has a central role in the formation and breakdown of physiological signaling molecules. In addition, a certain class of microbial epoxide hydrolases has recently been identified that is an integral part of a catabolic pathway, allowing the use of specific terpens as sole carbon sources. The recently available x-ray structures of a number of EHs mirror their respective functions: the microbial terpen EH differs in its fold from the canonical alpha/beta hydrolase fold of the xenobiotic-metabolizing mammalian EHs. It appears that the latter fold is the perfect solution for the efficient detoxification of a large variety of structurally different epoxides by a single enzyme, whereas the smaller microbial EH, which has a particularly high turnover number with its prefered substrate, seems to be the better solution for the hydrolysis of one specific substrate. The structure of the sEH also includes an additional catalytic domain that has recently been shown to possess phosphatase activity. Although the physiological substrate for this second active site has not been identified so far, the majority of known phosphatases are involved in signaling processes, suggesting that the sEH phosphatase domain also has a role in the regulation of physiological functions.