Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY829Z3)

• DOT Name: 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5)
• Synonyms: EC 2.3.1.51; Abhydrolase domain-containing protein 5; Lipid droplet-binding protein CGI-58
• Gene Name: ABHD5
• Related Disease:
  Dorfman-Chanarin disease
  Advanced cancer
  Cardiovascular disease
  Colon cancer
  Colon carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Exfoliative dermatitis
  Fatty liver disease
  Myopathy
  Neutral lipid storage myopathy
  Non-alcoholic fatty liver disease
  Non-syndromic ichthyosis
  Obesity
  Syndactyly
  Congenital ichthyosiform erythroderma
  Intestinal disorder
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Systemic primary carnitine deficiency disease
• UniProt ID: ABHD5_HUMAN
• EC Number: 2.3.1.51
• Pfam ID: PF00561
• Sequence:
  MAAEEEEVDSADTGERSGWLTGWLPTWCPTSISHLKEAEEKMLKCVPCTYKKEPVRISNG
  NKIWTLKFSHNISNKTPLVLLHGFGGGLGLWALNFGDLCTNRPVYAFDLLGFGRSSRPRF
  DSDAEEVENQFVESIEEWRCALGLDKMILLGHNLGGFLAAAYSLKYPSRVNHLILVEPWG
  FPERPDLADQDRPIPVWIRALGAALTPFNPLAGLRIAGPFGLSLVQRLRPDFKRKYSSMF
  EDDTVTEYIYHCNVQTPSGETAFKNMTIPYGWAKRPMLQRIGKMHPDIPVSVIFGARSCI
  DGNSGTSIQSLRPHSYVKTIAILGAGHYVYADQPEEFNQKVKEICDTVD
• Function: Coenzyme A-dependent lysophosphatidic acid acyltransferase that catalyzes the transfer of an acyl group on a lysophosphatidic acid. Functions preferentially with 1-oleoyl-lysophosphatidic acid followed by 1-palmitoyl-lysophosphatidic acid, 1-stearoyl-lysophosphatidic acid and 1-arachidonoyl-lysophosphatidic acid as lipid acceptor. Functions preferentially with arachidonoyl-CoA followed by oleoyl-CoA as acyl group donors. Functions in phosphatidic acid biosynthesis. May regulate the cellular storage of triacylglycerol through activation of the phospholipase PNPLA2. Involved in keratinocyte differentiation. Regulates lipid droplet fusion.
• Tissue Specificity: Widely expressed in various tissues, including lymphocytes, liver, skeletal muscle and brain. Expressed by upper epidermal layers and dermal fibroblasts in skin, hepatocytes and neurons (at protein level).
• KEGG Pathway: Regulation of lipolysis in adipocytes (hsa04923)
• Reactome Pathway: Triglyceride catabolism (R-HSA-163560)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dorfman-Chanarin disease	DISKKT3R	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[5]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Exfoliative dermatitis	DISQEWIW	Strong	Genetic Variation	[6]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[7]
Myopathy	DISOWG27	Strong	Genetic Variation	[8]
Neutral lipid storage myopathy	DISR9UYD	Strong	Genetic Variation	[9]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[10]
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Genetic Variation	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Syndactyly	DISZK2BT	Strong	Genetic Variation	[12]
Congenital ichthyosiform erythroderma	DISV8HQX	moderate	Genetic Variation	[13]
Intestinal disorder	DISGPMUQ	Limited	Genetic Variation	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]
Prostate cancer	DISF190Y	Limited	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[14]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[15]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[21]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[22]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[23]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[24]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[25]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[26]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[31]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 (ABHD5).	[29]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Macrophage ABHD5 Suppresses NFB-Dependent Matrix Metalloproteinase Expression and Cancer Metastasis.Cancer Res. 2019 Nov 1;79(21):5513-5526. doi: 10.1158/0008-5472.CAN-19-1059. Epub 2019 Aug 22.
• [3] Effect of Bariatric Weight Loss on the Adipose Lipolytic Transcriptome in Obese Humans.Mediators Inflamm. 2015;2015:106237. doi: 10.1155/2015/106237. Epub 2015 Nov 18.
• [4] ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2.Autophagy. 2016 Nov;12(11):2167-2182. doi: 10.1080/15548627.2016.1217380. Epub 2016 Aug 25.
• [5] Oncogenic role of ABHD5 in endometrial cancer.Cancer Manag Res. 2019 Mar 14;11:2139-2150. doi: 10.2147/CMAR.S188648. eCollection 2019.
• [6] Chanarin Dorfman syndrome: a case report with novel nonsense mutation.Gene. 2016 Jan 10;575(2 Pt 1):359-62. doi: 10.1016/j.gene.2015.09.004. Epub 2015 Sep 6.
• [7] Early onset of Chanarin-Dorfman syndrome with severe liver involvement in a patient with a complex rearrangement of ABHD5 promoter.BMC Med Genet. 2014 Mar 14;15:32. doi: 10.1186/1471-2350-15-32.
• [8] Inborn errors of cytoplasmic triglyceride metabolism.J Inherit Metab Dis. 2015 Jan;38(1):85-98. doi: 10.1007/s10545-014-9767-7. Epub 2014 Oct 10.
• [9] Neutral Lipid Storage Diseases as Cellular Model to Study Lipid Droplet Function. Cells. 2019 Feb 21;8(2):187. doi: 10.3390/cells8020187.
• [10] Inherited non-alcoholic fatty liver disease and dyslipidemia due to monoallelic ABHD5 mutations.J Hepatol. 2019 Aug;71(2):366-370. doi: 10.1016/j.jhep.2019.03.026. Epub 2019 Apr 4.
• [11] Macrophage CGI-58 deficiency promotes IL-1 transcription by activating the SOCS3-FOXO1 pathway.Clin Sci (Lond). 2015 Apr;128(8):493-506. doi: 10.1042/CS20140414.
• [12] Steatohepatitis and liver cirrhosis in Chanarin-Dorfman syndrome with a new ABDH5 mutation.Clin Res Hepatol Gastroenterol. 2012 Apr;36(2):e34-7. doi: 10.1016/j.clinre.2011.12.007. Epub 2012 Jan 13.
• [13] 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. doi: 10.1086/324121. Epub 2001 Oct 2.
• [14] Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5.BMC Cancer. 2017 Sep 6;17(1):631. doi: 10.1186/s12885-017-3589-6.
• [15] Clinical and genetic analysis of lipid storage myopathies.Muscle Nerve. 2009 Mar;39(3):333-42. doi: 10.1002/mus.21167.
• [16] In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol. 2016 Mar;90(3):677-89. doi: 10.1007/s00204-015-1483-z. Epub 2015 Feb 26.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [22] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [23] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [24] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [25] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [26] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [27] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.