High expression of the evolutionarily conserved α/β hydrolase domain containing 6 (ABHD6) in Ewing tumors

Max, Daniela; Hesse, Manuela; Volkmer, Ines; Staege, Martin S.

doi:10.1111/j.1349-7006.2009.01347.x

Cited by 30 publications

(31 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent evidence suggests that, like MAGL, ABHD6 can control the levels and signaling effi cacy of 2-AG in neurons ( 19,20 ). Overexpression of the two hydrolases has been found in certain types of cancer cells ( 12,18 ). However, in contrast to MAGL inhibition ( 12 ), knockdown of ABHD6 did not inhibit tumor cell growth ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)

Navia-Paldanius

Savinainen

Laitinen

2012

Journal of Lipid Research

152

199

View full text Add to dashboard Cite

amide, ester, and thioester bonds. The majority of serine hydrolases contain an ␣ / ␤ -hydrolase domain (ABHD) fold and use a Ser-His-Asp (SHD) triad for catalysis. Although several members of the metabolic serine hydrolase family are relatively well defined, the majority remain poorly characterized with respect to their physiological substrates and functions.Members of the metabolic serine family are also intimately involved in the generation and degradation of the endocannabinoid 2-arachidonoylyglycerol (C20:4) (2-AG). In brain regions endowed with 2-AG signaling, "on demand" biosynthesis of 2-AG occurs through phospholipase C ␤ -catalyzed cleavage of the membrane phospholipid phoshatidylinositol bisphosphate to generate sn-2-arachidonoyl-containing diacylglycerol (DAG) species, which are subsequently hydrolyzed by sn -1-specifi c lipases (DAGL ␣ and DAGL ␤ ) to generate 2-AG ( 3 ). The endocannabinoids are involved in a broad range of (patho)physiological processes, including neurotransmission, appetite, nociception, addiction, infl ammation, peripheral metabolism, and reproduction ( 4-6 ). The biological actions of 2-AG are mediated via two G protein-coupled receptors (CB1R and CB2R) that show unique and tissue-specifi c distribution. CB1R is highly enriched in the brain.The major enzymatic route for 2-AG inactivation is via hydrolysis, generating arachidonic acid (AA) and glycerol. In the CNS, three serine hydrolases, namely monoacylglycerol lipase (MAGL) and the ␣ / ␤ -hydrolase domain 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 ␣ / ␤ -hydrolase domain containing (ABHD)6 and ABHD12 remain poorly characterized. By applying a sensitive fl uorescent 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 fl uorophosphonate probe TAMRA-FP. However, the role of D278 and H306 as residues of the catalytic core of ABHD6 could not be verifi ed because none of the mutants showed detectable expression. Inhibitor profi ling revealed striking potency differences between hABHD6 and hABHD12, a fi nding that, when combined with the substrate profi ling data, should facilitate further efforts toward the design of potent and selective inhibitors, especially those targeting hABHD12, which currently lacks such inhibitors. The human serine hydrolases compris...

show abstract

Section: Discussionmentioning

confidence: 99%

“…ABHD6 is a ‫ف‬ 30 kDa integral membrane protein with high expression reported in certain forms of tumors ( 17,18 ). Based on hydropathy analysis and biochemical studies, ABHD6 appears to be an integral membrane protein whose active site is predicted to face the cell interior ( 7 ).…”

Section: Activity-based Protein Profi Ling Of Serine Hydrolasesmentioning

confidence: 99%

Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)

Navia-Paldanius

Savinainen

Laitinen

2012

Journal of Lipid Research

152

199

View full text Add to dashboard Cite

show abstract

“…Alpha-beta hydrolase containing 6 (ABHD6) is one of these genes. 59 In contrast to LIPI, ABHD6 seems to be regulated by EWSR1-ETS fusion proteins. 59,60 Nevertheless, TET-ETS negative tumors have also been shown to express ABHD6.…”

Section: Lipase H: a Second Lipase With High Expression In Ewing Tumorsmentioning

confidence: 99%

“…59 In contrast to LIPI, ABHD6 seems to be regulated by EWSR1-ETS fusion proteins. 59,60 Nevertheless, TET-ETS negative tumors have also been shown to express ABHD6. 5 Moreover, Epstein-Barr virus (EBV)-immortalized B-cells (so-called lymphoblastoid cell lines, LCL) express ABHD6.…”

Section: Lipase H: a Second Lipase With High Expression In Ewing Tumorsmentioning

confidence: 99%

Lipases and Related Molecules in Cancer

Staege

Hesse

Max

2010

Cancer�Growth�Metastasis

Self Cite

View full text Add to dashboard Cite

Lipases are enzymes that catalyze the hydrolysis of lipids. Based on protein structures and sequences, lipases can be classified into different protein families. The majority of conventional mammalian lipases are members of the protein super-families of serine esterases and alpha-beta hydrolases. Differential expression of lipases and related alpha-beta hydrolases in tumor cells has been observed. The physiological or patho-physiological functions of these tumor related enzymes are largely unknown. However, lipases are not only involved in energy metabolism but also in the metabolism of bioactive molecules, e.g. phosphatidic acid or arachidonic acid, suggesting that tumor-specifically expressed lipases might be interesting targets for the development of future treatment strategies. Moreover, independent of the patho-physiological function, tumor associated lipases can serve as targets for immunological treatment strategies. In addition, lipases with exclusive expression in single tumor entities can serve as potential diagnostic targets.

show abstract

“…Recent studies have shown that ABHD6 is highly expressed in several tumor cell lines, such as breast cancer cell line MCF7, but the significance of this high expression is not clear (Max et al, 2009). Another report demonstrated that inhibition of ABHD6 in brain produced the cannabnoid effect via accumulation of 2-AG, indicating the important roles of ABHD6 in regulating cell function (Marrs et al, 2010).…”

Section: Mag Lipasesmentioning

confidence: 99%

Monoacylglycerol as a Metabolic Coupling Factor in Glucose-Stimulated Insulin Secretion

Zhao¹,

Iglesias²,

Mugabo³

et al. 2013

Canadian Journal of Diabetes

View full text Add to dashboard Cite

In the present study we demonstrate that the obliterated GSIS due to lipolysis inhibition incells can be restored by providing exogenous MAG. In the -cells MAG levels increase significantly in the presence of high glucose concentration and specific inhibition of the major MAG hydrolase, abhydrolase-6 (ABHD6), in -cells and islets with WWL70 leads to accumulation of MAG with concomitant increase in insulin secretion. Lipidomics analysis v indicated that the major MAG species that is elevated by high glucose as well as WWL70addition is 1-stearoylglycerol (1-SG). Exogenously added 1-SG and also 1-palmitoylglycerol(1-PG) strongly enhanced GSIS and this augmentation is not dependent on the generation of FFA by these MAGs. This indicates that MAG is a potential candidate for being the lipid signal for GSIS amplification. Further evidence for this was provided by the observation that overexpression of the MAG hydrolase ABHD6 in INS832/13 cells, resulted in decreased insulin secretion, probably owing to the lowered MAG level inside the -cells.Pharmacological studies using AMG9810, a specific antagonist of transient receptor potential vanilloid-1 (TRPV1) receptor that binds MAG, revealed that a blockade of TRPV1 strongly attenuated the MAG-augmented insulin secretion. Since MAG is a potential activator of TRPV1, it is likely that MAG binds on the inner surface of the cell membrane to TRPV1, which in turn triggers rapid influx of Ca 2+ thereby promoting insulin granule exocytosis. Thus, AMG9810 was found to lower Ca 2+ influx into dispersed rat islet cells that was induced by high glucose and also WWL70.These results collectively suggest that MAG is the potential mediator of the lipid amplification of glucose-stimulated insulin secretion. Our results also indicate that pharmacological intervening at the ABHD6 hydrolysis step enhances insulin secretion; this enzyme protein can be a promising thrapeutic target for the development of anti-diabetic drugs that promote insulin secretion.

show abstract

High expression of the evolutionarily conserved α/β hydrolase domain containing 6 (ABHD6) in Ewing tumors

Cited by 30 publications

References 61 publications

Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)

Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)

Lipases and Related Molecules in Cancer

Monoacylglycerol as a Metabolic Coupling Factor in Glucose-Stimulated Insulin Secretion

Contact Info

Product

Resources

About