Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIK5GT5)

• DOT Name: Cytosolic phospholipase A2 gamma (PLA2G4C)
• Synonyms: cPLA2-gamma; EC 3.1.1.4; Cytosolic lysophospholipase; EC 3.1.1.5; Cytosolic lysophospholipid O-acyltransferase; EC 2.3.1.-; Phospholipase A2 group IVC
• Gene Name: PLA2G4C
• UniProt ID: PA24C_HUMAN
• EC Number: 2.3.1.-; 3.1.1.4; 3.1.1.5
• Pfam ID: PF01735
• Sequence:
  MGSSEVSIIPGLQKEEKAAVERRRLHVLKALKKLRIEADEAPVVAVLGSGGGLRAHIACL
  GVLSEMKEQGLLDAVTYLAGVSGSTWAISSLYTNDGDMEALEADLKHRFTRQEWDLAKSL
  QKTIQAARSENYSLTDFWAYMVISKQTRELPESHLSNMKKPVEEGTLPYPIFAAIDNDLQ
  PSWQEARAPETWFEFTPHHAGFSALGAFVSITHFGSKFKKGRLVRTHPERDLTFLRGLWG
  SALGNTEVIREYIFDQLRNLTLKGLWRRAVANAKSIGHLIFARLLRLQESSQGEHPPPED
  EGGEPEHTWLTEMLENWTRTSLEKQEQPHEDPERKGSLSNLMDFVKKTGICASKWEWGTT
  HNFLYKHGGIRDKIMSSRKHLHLVDAGLAINTPFPLVLPPTREVHLILSFDFSAGDPFET
  IRATTDYCRRHKIPFPQVEEAELDLWSKAPASCYILKGETGPVVMHFPLFNIDACGGDIE
  AWSDTYDTFKLADTYTLDVVVLLLALAKKNVRENKKKILRELMNVAGLYYPKDSARSCCL
  A
• Function: Calcium-independent phospholipase, lysophospholipase and O-acyltransferase involved in phospholipid remodeling with implications in endoplasmic reticulum membrane homeostasis and lipid droplet biogenesis. Preferentially hydrolyzes the ester bond of the fatty acyl group attached at the sn-2 position of phospholipids with choline and ethanolamine head groups, producing lysophospholipids that are used in deacylation-reacylation cycles. Transfers the sn-1 fatty acyl from one lysophospholipid molecule to the sn-2 position of another lysophospholipid to form diacyl, alkylacyl and alkenylacyl glycerophospholipids. Cleaves ester bonds but not alkyl or alkenyl ether bonds at sn-1 position of lysophospholipids. Catalyzes sn-2 fatty acyl transfer from phospholipids to the sn-2 position of 1-O-alkyl or 1-O-alkenyl lysophospholipids with lower efficiency. In response to dietary fatty acids, may play a role in the formation of nascent lipid droplets from the endoplasmic reticulum likely by regulating the phospholipid composition of these organelles ; (Microbial infection) May play a role in replication and assembly of human hepatitis C virus (HCV). In response to HCV infection, promotes remodeling of host endoplasmic reticulum membranes to form organelle-like structures called membranous web, where HCV replication occur. Can further mediate translocation of replication complexes to lipid droplets to enable virion assembly ; (Microbial infection) May facilitate human T-lymphotropic virus type 1 (HTLV-1) infection by promoting leukotriene B4 (LTB4) biosynthesis. LTB4 acts as a chemoattractant for HTLV-1-infected CD4-positive T cells and favors cell to cell viral transmission.
• Tissue Specificity: Highly expressed in heart and skeletal muscle.
• 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)
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Phospholipase D sig.ling pathway (hsa04072)
  Necroptosis (hsa04217)
  Vascular smooth muscle contraction (hsa04270)
  VEGF sig.ling pathway (hsa04370)
  Platelet activation (hsa04611)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Glutamatergic sy.pse (hsa04724)
  Serotonergic sy.pse (hsa04726)
  Long-term depression (hsa04730)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  GnRH sig.ling pathway (hsa04912)
  Ovarian steroidogenesis (hsa04913)
  Oxytocin sig.ling pathway (hsa04921)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Acyl chain remodelling of PE (R-HSA-1482839)
  Acyl chain remodelling of PI (R-HSA-1482922)
  Hydrolysis of LPC (R-HSA-1483115)
  Hydrolysis of LPE (R-HSA-1483152)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[2]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[10]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[14]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Cytosolic phospholipase A2 gamma (PLA2G4C).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytosolic phospholipase A2 gamma (PLA2G4C).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cytosolic phospholipase A2 gamma (PLA2G4C).	[12]

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] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [12] 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.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.