Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5CVDJM)

• DOT Name: Patatin-like phospholipase domain-containing protein 4 (PNPLA4)
• Synonyms: EC 3.1.1.3; Calcium-independent phospholipase A2-eta; iPLA2-eta; EC 3.1.1.4; Protein GS2
• Gene Name: PNPLA4
• UniProt ID: PLPL4_HUMAN
• EC Number: 3.1.1.3; 3.1.1.4
• Pfam ID: PF01734
• Sequence:
  MKHINLSFAACGFLGIYHLGAASALCRHGKKLVKDVKAFAGASAGSLVASVLLTAPEKIE
  ECNQFTYKFAEEIRRQSFGAVTPGYDFMARLRSGMESILPPSAHELAQNRLHVSITNAKT
  RENHLVSTFSSREDLIKVLLASSFVPIYAGLKLVEYKGQKWVDGGLTNALPILPVGRTVT
  ISPFSGRLDISPQDKGQLDLYVNIAKQDIMLSLANLVRLNQALFPPSKRKMESLYQCGFD
  DTVKFLLKENWFE
• Function: Has abundant triacylglycerol lipase activity. Transfers fatty acid from triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3-diacylglycerol from triglycerides. Additionally possesses acylglycerol transacylase and phospholipase A2 activities.
• Tissue Specificity: Expressed in all tissues examined, including heart, brain, placenta, lung, liver, muscle, kidney, pancreas and spleen.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Triglyceride catabolism (R-HSA-163560)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[7]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Patatin-like phospholipase domain-containing protein 4 (PNPLA4).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.