Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVXXJ5K)

• DOT Name: Phospholipase A and acyltransferase 3 (PLAAT3)
• Synonyms: EC 2.3.1.-; EC 3.1.1.32; EC 3.1.1.4; Adipose-specific phospholipase A2; AdPLA; Group XVI phospholipase A1/A2; H-rev 107 protein homolog; H-REV107; HREV107-1; HRAS-like suppressor 1; HRAS-like suppressor 3; HRSL3; HREV107-3; Renal carcinoma antigen NY-REN-65
• Gene Name: PLAAT3
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  HER2/NEU overexpressing breast cancer
  Lymphangioleiomyomatosis
  Neoplasm
  Ovarian cancer
  Prostate cancer
  Prostate carcinoma
  Metastatic malignant neoplasm
  Nasopharyngeal carcinoma
  Bone osteosarcoma
  Common cold
  Enterovirus infection
  Osteosarcoma
• UniProt ID: PLAT3_HUMAN
• PDB ID: 2KYT; 4DOT; 4FA0; 4Q95; 7C3Z; 7C41; 7ZOM
• EC Number: 2.3.1.-; 3.1.1.32; 3.1.1.4
• Pfam ID: PF04970
• Sequence:
  MRAPIPEPKPGDLIEIFRPFYRHWAIYVGDGYVVHLAPPSEVAGAGAASVMSALTDKAIV
  KKELLYDVAGSDKYQVNNKHDDKYSPLPCSKIIQRAEELVGQEVLYKLTSENCEHFVNEL
  RYGVARSDQVRDVIIAASVAGMGLAAMSLIGVMFSRNKRQKQ
• 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. For most substrates, PLA1 activity is much higher than PLA2 activity. 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). Exhibits high N-acyltransferase activity and low phospholipase A1/2 activity. Required for complete organelle rupture and degradation that occur during eye lens terminal differentiation, when fiber cells that compose the lens degrade all membrane-bound organelles in order to provide lens with transparency to allow the passage of light. Organelle membrane degradation is probably catalyzed by the phospholipase activity; (Microbial infection) Acts as a host factor for picornaviruses: required during early infection to promote viral genome release into the cytoplasm. May act as a cellular sensor of membrane damage at sites of virus entry, which relocalizes to sites of membrane rupture upon virus unfection. Facilitates safe passage of the RNA away from LGALS8, enabling viral genome translation by host ribosome. May also be involved in initiating pore formation, increasing pore size or in maintaining pores for genome delivery. The lipid-modifying enzyme activity is required for this process.
• Tissue Specificity: Widely expressed. low expression, if any, in hematopoietic cells and thymus. In testis, confined to round spermatids. Expressed in normal ovarian epithelial cells. Down-regulated in some ovarian carcinomas and testicular germ cell tumors. Highly expressed in white adipose tissue .
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Arachidonic acid metabolism (hsa00590)
  Linoleic acid metabolism (hsa00591)
  alpha-Linolenic acid metabolism (hsa00592)
  Metabolic pathways (hsa01100)
  Ras sig.ling pathway (hsa04014)
  Regulation of lipolysis in adipocytes (hsa04923)
• Reactome Pathway:
  Acyl chain remodelling of PS (R-HSA-1482801)
  Acyl chain remodelling of PE (R-HSA-1482839)
  Acyl chain remodelling of PI (R-HSA-1482922)
  Acyl chain remodelling of PC (R-HSA-1482788)
• BioCyc Pathway: MetaCyc:HS11053-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
HER2/NEU overexpressing breast cancer	DISYKID5	Strong	Altered Expression	[2]
Lymphangioleiomyomatosis	DISR0RNB	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Posttranslational Modification	[1]
Prostate carcinoma	DISMJPLE	Strong	Posttranslational Modification	[1]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[7]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[8]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[9]
Common cold	DIS3MADM	Limited	Biomarker	[10]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[11]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[9]

15 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 3 (PLAAT3).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[20]
Selenium	DM25CGV	Approved	Selenium increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[22]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholipase A and acyltransferase 3 (PLAAT3).	[25]

References

• [1] Screening of urine identifies PLA2G16 as a field defect methylation biomarker for prostate cancer detection.PLoS One. 2019 Jun 24;14(6):e0218950. doi: 10.1371/journal.pone.0218950. eCollection 2019.
• [2] High expression of PLA2G16 is associated with a better prognosis in HER2-positive breast cancer.J Thorac Dis. 2017 Apr;9(4):1002-1011. doi: 10.21037/jtd.2017.03.108.
• [3] Relationship between polymorphisms of the lipid metabolism-related gene PLA2G16 and risk of colorectal cancer in the Chinese population.Funct Integr Genomics. 2019 Mar;19(2):227-236. doi: 10.1007/s10142-018-0642-8. Epub 2018 Oct 20.
• [4] Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis.PLoS One. 2014 Oct 27;9(10):e104809. doi: 10.1371/journal.pone.0104809. eCollection 2014.
• [5] 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.
• [6] Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells.J Cell Sci. 2007 Apr 15;120(Pt 8):1393-404. doi: 10.1242/jcs.000018. Epub 2007 Mar 20.
• [7] PLA2G16 Expression in Human Osteosarcoma Is Associated with Pulmonary Metastasis and Poor Prognosis.PLoS One. 2015 May 18;10(5):e0127236. doi: 10.1371/journal.pone.0127236. eCollection 2015.
• [8] 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.
• [9] miR-142-5p suppresses proliferation and promotes apoptosis of human osteosarcoma cell line, HOS, by targeting PLA2G16 through the ERK1/2 signaling pathway.Oncol Lett. 2019 Jan;17(1):1363-1371. doi: 10.3892/ol.2018.9712. Epub 2018 Nov 15.
• [10] A reversible haploid mouse embryonic stem cell biobank resource for functional genomics.Nature. 2017 Oct 5;550(7674):114-118. doi: 10.1038/nature24027. Epub 2017 Sep 27.
• [11] Bypassing pan-enterovirus host factor PLA2G16.Nat Commun. 2019 Jul 18;10(1):3171. doi: 10.1038/s41467-019-11256-z.
• [12] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [13] 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.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [21] 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.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] 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.
• [24] 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.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.