Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR4990X)

• DOT Name: 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3)
• Synonyms: EC 2.3.1.51; Acylglycerol transacylase; Adiponutrin; ADPN; Calcium-independent phospholipase A2-epsilon; iPLA2-epsilon; EC 3.1.1.4; Lysophosphatidic acid acyltransferase; Patatin-like phospholipase domain-containing protein 3; EC 3.1.1.3
• Gene Name: PNPLA3
• UniProt ID: PLPL3_HUMAN
• EC Number: 2.3.1.51; 3.1.1.3; 3.1.1.4
• Pfam ID: PF01734
• Sequence:
  MYDAERGWSLSFAGCGFLGFYHVGATRCLSEHAPHLLRDARMLFGASAGALHCVGVLSGI
  PLEQTLQVLSDLVRKARSRNIGIFHPSFNLSKFLRQGLCKCLPANVHQLISGKIGISLTR
  VSDGENVLVSDFRSKDEVVDALVCSCFIPFYSGLIPPSFRGVRYVDGGVSDNVPFIDAKT
  TITVSPFYGEYDICPKVKSTNFLHVDITKLSLRLCTGNLYLLSRAFVPPDLKVLGEICLR
  GYLDAFRFLEEKGICNRPQPGLKSSSEGMDPEVAMPSWANMSLDSSPESAALAVRLEGDE
  LLDHLRLSILPWDESILDTLSPRLATALSEEMKDKGGYMSKICNLLPIRIMSYVMLPCTL
  PVESAIAIVQRLVTWLPDMPDDVLWLQWVTSQVFTRVLMCLLPASRSQMPVSSQQASPCT
  PEQDWPCWTPCSPKGCPAETKAEATPRSILRSSLNFFLGNKVPAGAEGLSTFPSFSLEKS
  L
• Function: Specifically catalyzes coenzyme A (CoA)-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to generate phosphatidic acid (PA), an important metabolic intermediate and precursor for both triglycerides and glycerophospholipids. Does not esterify other lysophospholipids. Acyl donors are long chain (at least C16) fatty acyl-CoAs: arachidonoyl-CoA, linoleoyl-CoA, oleoyl-CoA and at a lesser extent palmitoyl-CoA. Additionally possesses low triacylglycerol lipase and CoA-independent acylglycerol transacylase activities and thus may play a role in acyl-chain remodeling of triglycerides. In vitro may express hydrolytic activity against glycerolipids triacylglycerol, diacylglycerol and monoacylglycerol, with a strong preference for oleic acid as the acyl moiety. However, the triacylglycerol hydrolase activity is controversial and may be very low. Possesses phospholipase A2 activity.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Acyl chain remodeling of DAG and TAG (R-HSA-1482883)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[1]

20 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 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[12]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[18]
T0901317	DMZQVDI	Investigative	T0901317 increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[19]
CITCO	DM0N634	Investigative	CITCO increases the expression of 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3).	[10]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [10] Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way. Toxicol Appl Pharmacol. 2016 Jul 15;303:90-100. doi: 10.1016/j.taap.2016.05.006. Epub 2016 May 11.
• [11] 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.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] 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.
• [18] 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.
• [19] Isosilybin regulates lipogenesis and fatty acid oxidation via the AMPK/SREBP-1c/PPAR pathway. Chem Biol Interact. 2022 Dec 1;368:110250. doi: 10.1016/j.cbi.2022.110250. Epub 2022 Nov 5.