Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3M6P4)

• DOT Name: Phospholipase A and acyltransferase 1 (PLAAT1)
• Synonyms: EC 2.3.1.-; EC 3.1.1.32; EC 3.1.1.4; HRAS-like suppressor 1; HRSL1; Phospholipid-metabolizing enzyme A-C1
• Gene Name: PLAAT1
• Related Disease:
  Peptic ulcer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Coronary atherosclerosis
  Esophageal squamous cell carcinoma
  Familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Tuberculosis
  Bacterial infection
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
  Gastric cancer
  Cervical cancer
  Cervical carcinoma
  Neoplasm
• UniProt ID: PLAT1_HUMAN
• EC Number: 2.3.1.-; 3.1.1.32; 3.1.1.4
• Pfam ID: PF04970
• Sequence:
  MAFNDCFSLNYPGNPCPGDLIEVFRPGYQHWALYLGDGYVINIAPVDGIPASFTSAKSVF
  SSKALVKMQLLKDVVGNDTYRINNKYDETYPPLPVEEIIKRSEFVIGQEVAYNLLVNNCE
  HFVTLLRYGEGVSEQANRAISTVEFVTAAVGVFSFLGLFPKGQRAKYY
• Function: Exhibits both phospholipase A1/2 and acyltransferase activities. Shows phospholipase A1 (PLA1) and A2 (PLA2) activity, catalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids. Shows O-acyltransferase activity, catalyzing the transfer of a fatty acyl group from glycerophospholipid to the hydroxyl group of lysophospholipid. Shows N-acyltransferase activity, catalyzing the calcium-independent transfer of a fatty acyl group at the sn-1 position of phosphatidylcholine (PC) and other glycerophospholipids to the primary amine of phosphatidylethanolamine (PE), forming N-acylphosphatidylethanolamine (NAPE) which serves as precursor for N-acylethanolamines (NAEs).
• Tissue Specificity: .Abundantly expressed in testis, skeletal muscle, brain, and heart.; [Isoform 2]: Highly expressed in the testis, skeletal muscle, brain, heart, and thyroid.
• Reactome Pathway: Acyl chain remodelling of PE (R-HSA-1482839)
• BioCyc Pathway: MetaCyc:ENSG00000127252-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peptic ulcer	DISL8XZI	Definitive	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[5]
Familial hypercholesterolemia	DISC06IX	Strong	Altered Expression	[6]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Altered Expression	[6]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[7]
Bacterial infection	DIS5QJ9S	moderate	Altered Expression	[8]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[9]
Prostate cancer	DISF190Y	moderate	Biomarker	[10]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[10]
Gastric cancer	DISXGOUK	Disputed	Biomarker	[11]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[12]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]

11 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 Phospholipase A and acyltransferase 1 (PLAAT1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[23]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Phospholipase A and acyltransferase 1 (PLAAT1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Phospholipase A and acyltransferase 1 (PLAAT1).	[21]

References

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• [2] Association study of interferon-, cytosolic phospholipase A2, and cyclooxygenase-2 gene polymorphisms in Alzheimer disease.Am J Geriatr Psychiatry. 2010 Nov;18(11):983-7. doi: 10.1097/JGP.0b013e3181e70c05.
• [3] Proteolysis of apolipoprotein A-I by secretory phospholipase A? a new link between inflammation and atherosclerosis.J Biol Chem. 2014 Apr 4;289(14):10011-23. doi: 10.1074/jbc.M113.525717. Epub 2014 Feb 12.
• [4] Translational studies of lipoprotein-associated phospholipase A?in inflammation and atherosclerosis.J Am Coll Cardiol. 2012 Feb 21;59(8):764-72. doi: 10.1016/j.jacc.2011.11.019.
• [5] Association of single nucleotide polymorphisms in the prostaglandin-endoperoxide synthase 2 (PTGS2) and phospholipase A?group IIA (PLA2G2A) genes with susceptibility to esophageal squamous cell carcinoma.Asian Pac J Cancer Prev. 2014;15(4):1797-802. doi: 10.7314/apjcp.2014.15.4.1797.
• [6] Lipoprotein-associated phospholipase A?activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia.Nutr Metab Cardiovasc Dis. 2018 May;28(5):517-523. doi: 10.1016/j.numecd.2018.01.012. Epub 2018 Feb 2.
• [7] Structural basis for lipid binding and mechanism of the Mycobacterium tuberculosis Rv3802 phospholipase.J Biol Chem. 2018 Jan 26;293(4):1363-1372. doi: 10.1074/jbc.RA117.000240. Epub 2017 Dec 15.
• [8] Phospholipase A activity of adenylate cyclase toxin mediates translocation of its adenylate cyclase domain.Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):E6784-E6793. doi: 10.1073/pnas.1701783114. Epub 2017 Jul 31.
• [9] Promoter hypermethylation of CCNA1, RARRES1, and HRASLS3 in nasopharyngeal carcinoma.Oral Oncol. 2008 Apr;44(4):400-6. doi: 10.1016/j.oraloncology.2007.05.008. Epub 2007 Aug 3.
• [10] FAM84B promotes prostate tumorigenesis through a network alteration.Ther Adv Med Oncol. 2019 May 13;11:1758835919846372. doi: 10.1177/1758835919846372. eCollection 2019.
• [11] Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers.Cancer Res. 2004 Sep 15;64(18):6410-5. doi: 10.1158/0008-5472.CAN-04-1543.
• [12] Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: identification of candidate amplified and overexpressed genes.Genes Chromosomes Cancer. 2007 Apr;46(4):373-84. doi: 10.1002/gcc.20418.
• [13] Molecular interaction between K-Ras and H-REV107 in the Ras signaling pathway.Biochem Biophys Res Commun. 2017 Sep 16;491(2):257-264. doi: 10.1016/j.bbrc.2017.07.120. Epub 2017 Jul 22.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.