Home LiteratureArticle Details
PMID: 23328280 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Review

Mammalian alpha beta hydrolase domain (ABHD) proteins: Lipid metabolizing enzymes at the interface of cell signaling and energy metabolism.

Biochimica et biophysica acta ·Vol. 1831 ·No. 4 ·2013-04-00 ·Pages 792-802

Lord CC, Thomas G, Brown JM

Abstract

Dysregulation of lipid metabolism underlies many chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Therefore, understanding enzymatic mechanisms controlling lipid synthesis and degradation is imperative for successful drug discovery for these human diseases. Genes encoding α/β hydrolase fold domain (ABHD) proteins are present in virtually all reported genomes, and conserved structural motifs shared by these proteins predict common roles in lipid synthesis and degradation. However, the physiological substrates and products for these lipid metabolizing enzymes and their broader role in metabolic pathways remain largely uncharacterized. Recently, mutations in several members of the ABHD protein family have been implicated in inherited inborn errors of lipid metabolism. Furthermore, studies in cell and animal models have revealed important roles for ABHD proteins in lipid metabolism, lipid signal transduction, and metabolic disease. The purpose of this review is to provide a comprehensive summary surrounding the current state of knowledge regarding mammalian ABHD protein family members. In particular, we will discuss how ABHD proteins are ideally suited to act at the interface of lipid metabolism and signal transduction. Although, the current state of knowledge regarding mammalian ABHD proteins is still in its infancy, this review highlights the potential for the ABHD enzymes as being attractive targets for novel therapies targeting metabolic disease.

MeSH Terms
Animals Carboxylic Ester Hydrolases/genetics,metabolism Energy Metabolism/genetics,physiology Humans Lipid Metabolism/genetics,physiology Signal Transduction/genetics,physiology
Chemicals
Carboxylic Ester Hydrolases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Lord Caleb C
Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Thomas Gwynneth
Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Brown J Mark
Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
References (105)
105 references, click to expand
  1. The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors.
    Acta Physiol (Oxf). 2012 Feb;204(2):267-76 PMID: 21418147
  2. Multiple pathways involved in the biosynthesis of anandamide.
    Neuropharmacology. 2008 Jan;54(1):1-7 PMID: 17631919
  3. Analysis of lipolytic protein trafficking and interactions in adipocytes.
    J Biol Chem. 2007 Feb 23;282(8):5726-35 PMID: 17189257
  4. Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3.
    Orphanet J Rare Dis. 2012 Sep 02;7:59 PMID: 22938382
  5. CGI-58, the causative gene for Chanarin-Dorfman syndrome, mediates acylation of lysophosphatidic acid.
    J Biol Chem. 2008 Sep 5;283(36):24525-33 PMID: 18606822
  6. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells.
    Immunity. 2007 Dec;27(6):847-59 PMID: 18055230
  7. Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas.
    Int J Cancer. 2011 Dec 15;129(12):2855-66 PMID: 21400501
  8. Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for alpha/beta-hydrolase 4 in this pathway.
    J Biol Chem. 2006 Sep 8;281(36):26465-72 PMID: 16818490
  9. Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids.
    BMC Genomics. 2008 Feb 26;9:99 PMID: 18302766
  10. Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism.
    Am J Hum Genet. 2010 Sep 10;87(3):410-7 PMID: 20797687
  11. Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome.
    Am J Hum Genet. 2001 Nov;69(5):1002-12 PMID: 11590543
  12. Voluntary wheel running reverses age-induced changes in hippocampal gene expression.
    PLoS One. 2011;6(8):e22654 PMID: 21857943
  13. Genetic deletion of monoacylglycerol lipase alters endocannabinoid-mediated retrograde synaptic depression in the cerebellum.
    J Physiol. 2011 Oct 15;589(Pt 20):4847-55 PMID: 21911610
  14. The crystal structure of CCG1/TAF(II)250-interacting factor B (CIB).
    J Biol Chem. 2004 Mar 5;279(10):9615-24 PMID: 14672934
  15. Large-scale profiling of protein palmitoylation in mammalian cells.
    Nat Methods. 2009 Feb;6(2):135-8 PMID: 19137006
  16. An unannotated alpha/beta hydrolase superfamily member, ABHD6 differentially expressed among cancer cell lines.
    Mol Biol Rep. 2009 Apr;36(4):691-6 PMID: 18360779
  17. Intrinsic response of thoracic propriospinal neurons to axotomy.
    BMC Neurosci. 2010 Jun 04;11:69 PMID: 20525361
  18. EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides.
    J Lipid Res. 2012 Oct;53(10):2038-2045 PMID: 22798687
  19. Antisense oligonucleotides targeting abhydrolase domain containing 2 block human hepatitis B virus propagation.
    Oligonucleotides. 2011 Mar-Apr;21(2):77-84 PMID: 21466387
  20. Elevated mature macrophage expression of human ABHD2 gene in vulnerable plaque.
    Biochem Biophys Res Commun. 2008 Jan 11;365(2):207-13 PMID: 17980156
  21. Epigenetics Offer New Horizons for Colorectal Cancer Prevention.
    Curr Colorectal Cancer Rep. 2012 Mar;8(1):66-81 PMID: 22389639
  22. A comprehensive proteomics and genomics analysis reveals novel transmembrane proteins in human platelets and mouse megakaryocytes including G6b-B, a novel immunoreceptor tyrosine-based inhibitory motif protein.
    Mol Cell Proteomics. 2007 Mar;6(3):548-64 PMID: 17186946
  23. Cell proliferation and interleukin-6-type cytokine signaling are implicated by gene expression responses in early optic nerve head injury in rat glaucoma.
    Invest Ophthalmol Vis Sci. 2011 Jan 25;52(1):504-18 PMID: 20847120
  24. Sensing of lysophospholipids by TRPC5 calcium channel.
    J Biol Chem. 2006 Feb 24;281(8):4977-82 PMID: 16368680
  25. CpG island methylation profiling in human salivary gland adenoid cystic carcinoma.
    Cancer. 2011 Jul 1;117(13):2898-909 PMID: 21692051
  26. In silico analysis of T-bet activity in peripheral blood mononuclear cells in patients with inflammatory bowel disease (IBD).
    In Silico Biol. 2009;9(5-6):355-63 PMID: 22430437
  27. G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine.
    J Biol Chem. 2004 Oct 8;279(41):42484-91 PMID: 15280385
  28. Alpha/beta hydrolase fold enzymes: the family keeps growing.
    Curr Opin Struct Biol. 1999 Dec;9(6):732-7 PMID: 10607665
  29. The alpha/beta hydrolase fold.
    Protein Eng. 1992 Apr;5(3):197-211 PMID: 1409539
  30. Intestinal activation of Notch signaling induces rapid onset hepatic steatosis and insulin resistance.
    PLoS One. 2011;6(6):e20767 PMID: 21698231
  31. Gene expression profiling in a mouse model for African trypanosomiasis.
    Genes Immun. 2006 Dec;7(8):667-79 PMID: 17066074
  32. A new cluster of genes within the human major histocompatibility complex.
    Science. 1989 Jan 13;243(4888):214-7 PMID: 2911734
  33. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.
    Chem Biol. 2007 Dec;14(12):1347-56 PMID: 18096503
  34. Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.
    Cancer Res. 2006 Jun 15;66(12):6080-6 PMID: 16778180
  35. Proteome profile of functional mitochondria from human skeletal muscle using one-dimensional gel electrophoresis and HPLC-ESI-MS/MS.
    J Proteomics. 2009 Aug 20;72(6):1046-60 PMID: 19567276
  36. Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58).
    J Biol Chem. 2010 Mar 5;285(10):7300-11 PMID: 20023287
  37. Effects of rosiglitazone and high fat diet on lipase/esterase expression in adipose tissue.
    Biochim Biophys Acta. 2007 Feb;1771(2):177-84 PMID: 17215164
  38. CGI-58/ABHD5 is a coenzyme A-dependent lysophosphatidic acid acyltransferase.
    J Lipid Res. 2010 Apr;51(4):709-19 PMID: 19801371
  39. Increase of smooth muscle cell migration and of intimal hyperplasia in mice lacking the alpha/beta hydrolase domain containing 2 gene.
    Biochem Biophys Res Commun. 2005 Apr 1;329(1):296-304 PMID: 15721306
  40. The emerging role of human esterases.
    Drug Metab Pharmacokinet. 2012;27(5):466-77 PMID: 22813719
  41. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase.
    Science. 2006 May 5;312(5774):734-7 PMID: 16675698
  42. Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening.
    Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20941-6 PMID: 21084632
  43. Intermittent hypoxia mobilizes bone marrow-derived very small embryonic-like stem cells and activates developmental transcriptional programs in mice.
    Sleep. 2010 Nov;33(11):1439-46 PMID: 21102985
  44. The 47kDa Akt substrate associates with phosphodiesterase 3B and regulates its level in adipocytes.
    Biochem Biophys Res Commun. 2006 Apr 21;342(4):1218-22 PMID: 16516160
  45. Mutant huntingtin activates Nrf2-responsive genes and impairs dopamine synthesis in a PC12 model of Huntington's disease.
    BMC Mol Biol. 2008 Oct 09;9:84 PMID: 18844975
  46. Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12).
    J Lipid Res. 2012 Nov;53(11):2413-24 PMID: 22969151
  47. Cellular target genes of Epstein-Barr virus nuclear antigen 2.
    J Virol. 2006 Oct;80(19):9761-71 PMID: 16973580
  48. Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases.
    Clin Exp Metastasis. 2011 Oct;28(7):637-47 PMID: 21681495
  49. Novel insulin-elicited phosphoproteins in adipocytes.
    Cell Signal. 2005 Jan;17(1):59-66 PMID: 15451025
  50. Discovery and validation of 3 novel DNA methylation markers of prostate cancer prognosis.
    J Urol. 2007 May;177(5):1753-8 PMID: 17437806
  51. Clinical omics analysis of colorectal cancer incorporating copy number aberrations and gene expression data.
    Cancer Inform. 2010 Jul 29;9:147-61 PMID: 20706620
  52. Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray.
    Cancer Sci. 2006 Jan;97(1):64-71 PMID: 16367923
  53. Adipose-selective overexpression of ABHD5/CGI-58 does not increase lipolysis or protect against diet-induced obesity.
    J Lipid Res. 2011 Nov;52(11):2032-42 PMID: 21885429
  54. Molecular cytogenetic characterization of t(14;19)(q32;p13), a new recurrent translocation in B cell malignancies.
    Virchows Arch. 2007 May;450(5):559-65 PMID: 17406891
  55. High expression of the evolutionarily conserved alpha/beta hydrolase domain containing 6 (ABHD6) in Ewing tumors.
    Cancer Sci. 2009 Dec;100(12):2383-9 PMID: 19793082
  56. Neutral lipid storage disease: a genetic disorder with abnormalities in the regulation of phospholipid metabolism.
    J Lipid Res. 1998 Jan;39(1):31-43 PMID: 9469583
  57. Competitive activity-based protein profiling identifies aza-β-lactams as a versatile chemotype for serine hydrolase inhibition.
    J Am Chem Soc. 2012 Mar 21;134(11):5068-71 PMID: 22400490
  58. Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1).
    J Biol Chem. 2009 Jul 31;284(31):20927-35 PMID: 19525223
  59. Using transcription modules to identify expression clusters perturbed in Williams-Beuren syndrome.
    PLoS Comput Biol. 2011 Jan 20;7(1):e1001054 PMID: 21304579
  60. Cloning and tissue distribution of three murine alpha/beta hydrolase fold protein cDNAs.
    Biochem Biophys Res Commun. 2002 Apr 5;292(3):617-25 PMID: 11922611
  61. Dorz1, a novel gene expressed in differentiating cerebellar granule neurons, is down-regulated in Zic1-deficient mouse.
    Brain Res Mol Brain Res. 2003 Dec 12;120(1):57-64 PMID: 14667578
  62. Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours.
    Oncogene. 2011 Oct 13;30(41):4243-60 PMID: 21552290
  63. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.
    Nat Genet. 2011 Oct 16;43(11):1131-8 PMID: 22001757
  64. Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids.
    Nat Chem Biol. 2011 Sep 18;7(11):763-5 PMID: 21926997
  65. CGI-58/ABHD5-derived signaling lipids regulate systemic inflammation and insulin action.
    Diabetes. 2012 Feb;61(2):355-63 PMID: 22228714
  66. Regulation of AMP-activated protein kinase by cAMP in adipocytes: roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis.
    Cell Signal. 2009 May;21(5):760-6 PMID: 19167487
  67. Organophosphate-sensitive lipases modulate brain lysophospholipids, ether lipids and endocannabinoids.
    Chem Biol Interact. 2008 Sep 25;175(1-3):355-64 PMID: 18495101
  68. DNA methylation of the PITX2 gene promoter region is a strong independent prognostic marker of biochemical recurrence in patients with prostate cancer after radical prostatectomy.
    J Urol. 2009 Apr;181(4):1678-85 PMID: 19233404
  69. Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver.
    J Biol Chem. 2012 Mar 16;287(12):9240-9 PMID: 22294686
  70. Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5.
    Am J Physiol Endocrinol Metab. 2009 Aug;297(2):E289-96 PMID: 19401457
  71. Identification of genes directly regulated by the oncogene ZNF217 using chromatin immunoprecipitation (ChIP)-chip assays.
    J Biol Chem. 2007 Mar 30;282(13):9703-9712 PMID: 17259635
  72. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
    Nat Neurosci. 2010 Aug;13(8):951-7 PMID: 20657592
  73. Distinct roles for alpha-beta hydrolase domain 5 (ABHD5/CGI-58) and adipose triglyceride lipase (ATGL/PNPLA2) in lipid metabolism and signaling.
    Adipocyte. 2012;1(3):123-131 PMID: 23145367
  74. CGI-58 facilitates lipolysis on lipid droplets but is not involved in the vesiculation of lipid droplets caused by hormonal stimulation.
    J Lipid Res. 2007 May;48(5):1078-89 PMID: 17308334
  75. Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region.
    Genomics. 2004 Jan;83(1):153-67 PMID: 14667819
  76. Role of epoxide hydrolases in lipid metabolism.
    Biochimie. 2013 Jan;95(1):91-5 PMID: 22722082
  77. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome.
    Cell Metab. 2006 May;3(5):309-19 PMID: 16679289
  78. COX-2 and fatty acid amide hydrolase can regulate the time course of depolarization-induced suppression of excitation.
    Br J Pharmacol. 2011 Nov;164(6):1672-83 PMID: 21564090
  79. Prediction of human disease genes by human-mouse conserved coexpression analysis.
    PLoS Comput Biol. 2008 Mar 28;4(3):e1000043 PMID: 18369433
  80. Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B.
    Proc Natl Acad Sci U S A. 1989 Nov;86(22):8955-8 PMID: 2813433
  81. Acylglycerol recycling from triacylglycerol to phospholipid, not lipase activity, is defective in neutral lipid storage disease fibroblasts.
    J Biol Chem. 1996 Jul 12;271(28):16644-51 PMID: 8663220
  82. Neutral lipid storage disease with fatty liver and cholestasis.
    J Pediatr Gastroenterol Nutr. 1997 Nov;25(5):541-7 PMID: 9360211
  83. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance.
    J Lipid Res. 2010 Nov;51(11):3306-15 PMID: 20802159
  84. A genome wide shRNA screen identifies α/β hydrolase domain containing 4 (ABHD4) as a novel regulator of anoikis resistance.
    Apoptosis. 2012 Jul;17(7):666-78 PMID: 22488300
  85. Identification of additional transcripts in the Williams-Beuren syndrome critical region.
    Hum Genet. 2002 May;110(5):429-38 PMID: 12073013
  86. Identification and association analysis of several hundred single nucleotide polymorphisms within candidate genes for back fat thickness in Italian Large White pigs using a selective genotyping approach.
    J Anim Sci. 2012 Aug;90(8):2450-64 PMID: 22367074
  87. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.
    PLoS Genet. 2012;8(2):e1002490 PMID: 22359512
  88. Human lymphocyte antigen B-associated transcript 2, 3, and 5 polymorphisms and haplotypes are associated with susceptibility of Kawasaki disease and coronary artery aneurysm.
    J Clin Lab Anal. 2010;24(4):262-8 PMID: 20626023
  89. Alpha/beta hydrolase 1 is upregulated in D5 dopamine receptor knockout mice and reduces O2- production of NADPH oxidase.
    Biochem Biophys Res Commun. 2009 Jan 30;379(1):81-5 PMID: 19073140
  90. Perilipin A mediates the reversible binding of CGI-58 to lipid droplets in 3T3-L1 adipocytes.
    J Biol Chem. 2004 Oct 1;279(40):42062-71 PMID: 15292255
  91. Global profiling of dynamic protein palmitoylation.
    Nat Methods. 2011 Nov 06;9(1):84-9 PMID: 22056678
  92. Transcriptome analysis of in vivo and in vitro matured bovine MII oocytes.
    Theriogenology. 2009 Apr 1;71(6):939-46 PMID: 19150733
  93. Circadian variations in rat liver gene expression: relationships to drug actions.
    J Pharmacol Exp Ther. 2008 Sep;326(3):700-16 PMID: 18562560
  94. Dual inhibition of alpha/beta-hydrolase domain 6 and fatty acid amide hydrolase increases endocannabinoid levels in neurons.
    J Biol Chem. 2011 Aug 19;286(33):28723-28728 PMID: 21665953
  95. Efficient inhibition of miR-155 function in vivo by peptide nucleic acids.
    Nucleic Acids Res. 2010 Jul;38(13):4466-75 PMID: 20223773
  96. Age-related pulmonary emphysema in mice lacking alpha/beta hydrolase domain containing 2 gene.
    Biochem Biophys Res Commun. 2009 Mar 6;380(2):419-24 PMID: 19250629
  97. Activation of the endocannabinoid system by organophosphorus nerve agents.
    Nat Chem Biol. 2008 Jun;4(6):373-8 PMID: 18438404
  98. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression.
    Cell. 2011 May 13;145(4):571-83 PMID: 21565614
  99. Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling.
    Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41 PMID: 18657971
  100. Activity-based proteomics: identification of ABHD11 and ESD activities as potential biomarkers for human lung adenocarcinoma.
    J Proteomics. 2011 Sep 6;74(10):1884-94 PMID: 21596165
  101. Copy number analysis identifies novel interactions between genomic loci in ovarian cancer.
    PLoS One. 2010 Sep 10;5(9): PMID: 20844748
  102. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
    Hum Genet. 2012 Apr;131(4):565-79 PMID: 21996756
  103. Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors.
    Nat Chem Biol. 2011 May 15;7(7):469-78 PMID: 21572424
  104. Determining signalling nodes for apoptosis by a genetic high-throughput screen.
    PLoS One. 2011;6(9):e25023 PMID: 21966401
  105. CGI-58 interacts with perilipin and is localized to lipid droplets. Possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome.
    J Biol Chem. 2004 Jul 16;279(29):30490-7 PMID: 15136565
Article Info
Journal
Biochimica et biophysica acta
Abbr.
Biochim Biophys Acta
ISSN
0006-3002
DOI
10.1016/j.bbalip.2013.01.002
Published
2013-04-00
Epub
2013-00-14
Pages
792-802
Language
English
Region
Netherlands
NLM ID
0217513
PMCID
PMC4765316
Subset
IM
Grants
NHLBI NIH HHS · R00 HL096166 · United States
NHLBI NIH HHS · R01 HL122283 · United States
NHLBI NIH HHS · T32 HL091797 · United States
NHLBI NIH HHS · R00-HL096166 · United States
External Links
PubMed source DOI: 10.1016/j.bbalip.2013.01.002 PMC Full Text
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2