Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5I4Y9K)

• DOT Name: 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)
• Synonyms: EC 2.3.1.51; 1-acylglycerol-3-phosphate O-acyltransferase 2; 1-AGP acyltransferase 2; 1-AGPAT 2; Lysophosphatidic acid acyltransferase beta; LPAAT-beta
• Gene Name: AGPAT2
• Related Disease:
  Congenital generalized lipodystrophy type 1
  Berardinelli-Seip congenital lipodystrophy
  Neonatal diabetes mellitus
• UniProt ID: PLCB_HUMAN
• EC Number: 2.3.1.51
• Pfam ID: PF01553
• Sequence:
  MELWPCLAAALLLLLLLVQLSRAAEFYAKVALYCALCFTVSAVASLVCLLRHGGRTVENM
  SIIGWFVRSFKYFYGLRFEVRDPRRLQEARPCVIVSNHQSILDMMGLMEVLPERCVQIAK
  RELLFLGPVGLIMYLGGVFFINRQRSSTAMTVMADLGERMVRENLKVWIYPEGTRNDNGD
  LLPFKKGAFYLAVQAQVPIVPVVYSSFSSFYNTKKKFFTSGTVTVQVLEAIPTSGLTAAD
  VPALVDTCHRAMRTTFLHISKTPQENGATAGSGVQPAQ
• Function: Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone.
• Tissue Specificity: Expressed predominantly in adipose tissue, pancreas and liver.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  Phospholipase D sig.ling pathway (hsa04072)
  Fat digestion and absorption (hsa04975)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Synthesis of PA (R-HSA-1483166)
• BioCyc Pathway: MetaCyc:HS09990-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital generalized lipodystrophy type 1	DISIDEEW	Strong	Autosomal recessive	[1]
Berardinelli-Seip congenital lipodystrophy	DISKW75N	Supportive	Autosomal recessive	[2]
Neonatal diabetes mellitus	DISFHF9K	Limited	Autosomal recessive	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2) decreases the response to substance of Arsenic trioxide.	[27]
Capecitabine	DMTS85L	Approved	1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2) increases the response to substance of Capecitabine.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[16]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[17]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[24]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[25]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[25]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[26]
CITCO	DM0N634	Investigative	CITCO increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2).	[25]

References

• [1] AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002 May;31(1):21-3. doi: 10.1038/ng880. Epub 2002 Apr 22.
• [2] Berardinelli-Seip Congenital Lipodystrophy. 2003 Sep 8 [updated 2016 Dec 8]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] 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.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] 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.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [17] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [18] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [26] Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells. Toxicol In Vitro. 2022 Feb;78:105268. doi: 10.1016/j.tiv.2021.105268. Epub 2021 Oct 29.
• [27] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [28] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.