Details of Drug Off-Target (DOT)

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

• DOT Name: Monoacylglycerol lipase ABHD2 (ABHD2)
• Synonyms: EC 3.1.1.23; 2-arachidonoylglycerol hydrolase; Abhydrolase domain-containing protein 2; Acetylesterase; EC 3.1.1.6; Lung alpha/beta hydrolase 2; Progesterone-sensitive lipase; EC 3.1.1.79; Protein PHPS1-2
• Gene Name: ABHD2
• Related Disease:
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Age-related macular degeneration
  Arteriosclerosis
  Atherosclerosis
  Coronary heart disease
  Epithelial ovarian cancer
  Hyperlipidemia
  leukaemia
  Leukemia
  Ovarian cancer
  Ovarian neoplasm
  Chronic obstructive pulmonary disease
  Influenza
  Pulmonary emphysema
  Stroke
• UniProt ID: ABHD2_HUMAN
• EC Number: 3.1.1.23; 3.1.1.6; 3.1.1.79
• Pfam ID: PF00561
• Sequence:
  MNAMLETPELPAVFDGVKLAAVAAVLYVIVRCLNLKSPTAPPDLYFQDSGLSRFLLKSCP
  LLTKEYIPPLIWGKSGHIQTALYGKMGRVRSPHPYGHRKFITMSDGATSTFDLFEPLAEH
  CVGDDITMVICPGIANHSEKQYIRTFVDYAQKNGYRCAVLNHLGALPNIELTSPRMFTYG
  CTWEFGAMVNYIKKTYPLTQLVVVGFSLGGNIVCKYLGETQANQEKVLCCVSVCQGYSAL
  RAQETFMQWDQCRRFYNFLMADNMKKIILSHRQALFGDHVKKPQSLEDTDLSRLYTATSL
  MQIDDNVMRKFHGYNSLKEYYEEESCMRYLHRIYVPLMLVNAADDPLVHESLLTIPKSLS
  EKRENVMFVLPLHGGHLGFFEGSVLFPEPLTWMDKLVVEYANAICQWERNKLQCSDTEQV
  EADLE
• Function: Progesterone-dependent acylglycerol lipase that catalyzes hydrolysis of endocannabinoid arachidonoylglycerol (AG) from cell membrane. Acts as a progesterone receptor: progesterone-binding activates the acylglycerol lipase activity, mediating degradation of 1-arachidonoylglycerol (1AG) and 2-arachidonoylglycerol (2AG) to glycerol and arachidonic acid (AA). Also displays an ester hydrolase activity against acetyl ester, butanoate ester and hexadecanoate ester. Plays a key role in sperm capacitation in response to progesterone by mediating degradation of 2AG, an inhibitor of the sperm calcium channel CatSper, leading to calcium influx via CatSper and sperm activation. May also play a role in smooth muscle cells migration.
• Tissue Specificity: Present in sperm (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[3]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[3]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[4]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[5]
leukaemia	DISS7D1V	Strong	Altered Expression	[6]
Leukemia	DISNAKFL	Strong	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[4]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[7]
Influenza	DIS3PNU3	moderate	Biomarker	[8]
Pulmonary emphysema	DIS5M7HZ	moderate	Biomarker	[7]
Stroke	DISX6UHX	moderate	Genetic Variation	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Monoacylglycerol lipase ABHD2 (ABHD2) affects the response to substance of Cisplatin.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Monoacylglycerol lipase ABHD2 (ABHD2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Monoacylglycerol lipase ABHD2 (ABHD2).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Monoacylglycerol lipase ABHD2 (ABHD2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[17]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[18]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[17]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[19]
Estrone	DM5T6US	Approved	Estrone increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[17]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[22]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[26]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Monoacylglycerol lipase ABHD2 (ABHD2).	[27]

References

• [1] Abhydrolase domain containing 2, an androgen target gene, promotes prostate cancer cell proliferation and migration.Eur J Cancer. 2016 Apr;57:39-49. doi: 10.1016/j.ejca.2016.01.002. Epub 2016 Feb 6.
• [2] Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):4027-4038. doi: 10.1167/iovs.17-21734.
• [3] Regulation of MFGE8 by the intergenic coronary artery disease locus on 15q26.1.Atherosclerosis. 2019 May;284:11-17. doi: 10.1016/j.atherosclerosis.2019.02.012. Epub 2019 Feb 22.
• [4] Suppression of ABHD2, identified through a functional genomics screen, causes anoikis resistance, chemoresistance and poor prognosis in ovarian cancer.Oncotarget. 2016 Jul 26;7(30):47620-47636. doi: 10.18632/oncotarget.9951.
• [5] Weighted Gene Co-Expression Network Analysis Identifies Specific Modules and Hub Genes Related to Hyperlipidemia.Cell Physiol Biochem. 2018;48(3):1151-1163. doi: 10.1159/000491982. Epub 2018 Jul 25.
• [6] O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia.J Exp Med. 2013 Apr 8;210(4):805-19. doi: 10.1084/jem.20121482. Epub 2013 Mar 11.
• [7] Associations of ABHD2 genetic variations with risks for chronic obstructive pulmonary disease in a Chinese Han population.PLoS One. 2015 Apr 16;10(4):e0123929. doi: 10.1371/journal.pone.0123929. eCollection 2015.
• [8] Down-regulation of the expression of O-acetyl-GD3 by the O-acetylesterase cDNA in hamster melanoma cells: effects on cellular proliferation, differentiation, and melanogenesis.J Neurochem. 1999 Mar;72(3):954-61. doi: 10.1046/j.1471-4159.1999.0720954.x.
• [9] Genome-wide association analysis of ischemic stroke in young adults.G3 (Bethesda). 2011 Nov;1(6):505-14. doi: 10.1534/g3.111.001164. Epub 2011 Nov 1.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] 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.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [18] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [19] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [25] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [28] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.