Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN4HEJ4)

• DOT Name: Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1)
• Synonyms: 2-acylglycerophosphocholine O-acyltransferase; EC 2.3.1.62; Acyl-CoA:monoacylglycerol acyltransferase LPGAT1; EC 2.3.1.22; Lysophospholipid acyltransferase 7; LPLAT7; EC 2.3.1.-; Stearoyl-CoA:1-lyso-2-acyl-PE acyltransferase
• Gene Name: LPGAT1
• Related Disease:
  Major depressive disorder
  Obesity
• UniProt ID: LGAT1_HUMAN
• EC Number: 2.3.1.-; 2.3.1.22; 2.3.1.62
• Pfam ID: PF16076 ; PF01553
• Sequence:
  MAITLEEAPWLGWLLVKALMRFAFMVVNNLVAIPSYICYVIILQPLRVLDSKRFWYIEGI
  MYKWLLGMVASWGWYAGYTVMEWGEDIKAVSKDEAVMLVNHQATGDVCTLMMCLQDKGLV
  VAQMMWLMDHIFKYTNFGIVSLVHGDFFIRQGRSYRDQQLLLLKKHLENNYRSRDRKWIV
  LFPEGGFLRKRRETSQAFAKKNNLPFLTNVTLPRSGATKIILNALVAQQKNGSPAGGDAK
  ELDSKSKGLQWIIDTTIAYPKAEPIDIQTWILGYRKPTVTHVHYRIFPIKDVPLETDDLT
  TWLYQRFVEKEDLLSHFYETGAFPPSKGHKEAVSREMTLSNLWIFLIQSFAFLSGYMWYN
  IIQYFYHCLF
• Function: Lysophospholipid acyltransferase involved in fatty acyl chain remodeling of glycerophospholipids in the endoplasmic reticulum membrane. Selectively catalyzes the transfer and esterification of saturated long-chain fatty acids from acyl-CoA to the sn-1 position of 1-lyso-2-acyl phosphatidylethanolamines (1-lyso-PE, LPE), with a preference for stearoyl CoA over palmitoyl CoA as acyl donor. Acts in concert with an unknown phospholipase A1 to convert palmitate phosphatidylethanolamine (PE) species into stearate ones. Provides substrates to the PE methylation pathway, controlling stearate/palmitate composition of PE and phosphatidylcholine (PC) species with an overall impact on de novo hepatic lipid synthesis, body fat content and life span. Can acylate lysophosphatidylglycerols (LPG) using various saturated fatty acyl-CoAs as acyl donors. Can also acylate monoacylglycerols with a preference for 2-monoacylglycerols over 1-monoacylglycerols. Has no activity toward lysophosphatidic acids (LPA).
• Tissue Specificity: Highly expressed in liver and placenta. Also expressed in peripheral blood, lung, kidney and brain. Detected at lower levels in colon. High expression is detected in brain and testis.
• KEGG Pathway: Glycerophospholipid metabolism (hsa00564)
• Reactome Pathway: Acyl chain remodelling of PG (R-HSA-1482925)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Obesity	DIS47Y1K	Strong	Biomarker	[2]

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 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[18]

15 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 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[14]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 (LPGAT1).	[20]

References

• [1] Molecular Genetic Analysis Subdivided by Adversity Exposure Suggests Etiologic Heterogeneity in Major Depression.Am J Psychiatry. 2018 Jun 1;175(6):545-554. doi: 10.1176/appi.ajp.2017.17060621. Epub 2018 Mar 2.
• [2] Evidence for a role of LPGAT1 in influencing BMI and percent body fat in Native Americans.Obesity (Silver Spring). 2013 Jan;21(1):193-202. doi: 10.1002/oby.20243.
• [3] 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.
• [4] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] 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.
• [8] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [9] 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.
• [10] 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.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.