Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE70SOT)

• DOT Name: Cytosolic phospholipase A2 (PLA2G4A)
• Synonyms: cPLA2; Phospholipase A2 group IVA
• Gene Name: PLA2G4A
• Related Disease:
  Cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder
  Cryptogenic multifocal ulcerous stenosing enteritis
• UniProt ID: PA24A_HUMAN
• PDB ID: 1BCI; 1CJY; 1RLW
• EC Number: 3.1.1.4; 3.1.1.5
• Pfam ID: PF00168 ; PF01735
• Sequence:
  MSFIDPYQHIIVEHQYSHKFTVVVLRATKVTKGAFGDMLDTPDPYVELFISTTPDSRKRT
  RHFNNDINPVWNETFEFILDPNQENVLEITLMDANYVMDETLGTATFTVSSMKVGEKKEV
  PFIFNQVTEMVLEMSLEVCSCPDLRFSMALCDQEKTFRQQRKEHIRESMKKLLGPKNSEG
  LHSARDVPVVAILGSGGGFRAMVGFSGVMKALYESGILDCATYVAGLSGSTWYMSTLYSH
  PDFPEKGPEEINEELMKNVSHNPLLLLTPQKVKRYVESLWKKKSSGQPVTFTDIFGMLIG
  ETLIHNRMNTTLSSLKEKVNTAQCPLPLFTCLHVKPDVSELMFADWVEFSPYEIGMAKYG
  TFMAPDLFGSKFFMGTVVKKYEENPLHFLMGVWGSAFSILFNRVLGVSGSQSRGSTMEEE
  LENITTKHIVSNDSSDSDDESHEPKGTENEDAGSDYQSDNQASWIHRMIMALVSDSALFN
  TREGRAGKVHNFMLGLNLNTSYPLSPLSDFATQDSFDDDELDAAVADPDEFERIYEPLDV
  KSKKIHVVDSGLTFNLPYPLILRPQRGVDLIISFDFSARPSDSSPPFKELLLAEKWAKMN
  KLPFPKIDPYVFDREGLKECYVFKPKNPDMEKDCPTIIHFVLANINFRKYRAPGVPRETE
  EEKEIADFDIFDDPESPFSTFNFQYPNQAFKRLHDLMHFNTLNNIDVIKEAMVESIEYRR
  QNPSRCSVSLSNVEARRFFNKEFLSKPKA
• Function: Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response. Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production. Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway. In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids. Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific. Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides. Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis.
• Tissue Specificity: Expressed in various cells and tissues such as macrophages, neutrophils, fibroblasts and lung endothelium. Expressed in platelets (at protein level) .
• 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 PC (R-HSA-1482788)
  Acyl chain remodeling of CL (R-HSA-1482798)
  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 PG (R-HSA-1482925)
  Hydrolysis of LPC (R-HSA-1483115)
  Synthesis of PA (R-HSA-1483166)
  Arachidonic acid metabolism (R-HSA-2142753)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  Platelet sensitization by LDL (R-HSA-432142)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  phospho-PLA2 pathway (R-HSA-111995)
• BioCyc Pathway: MetaCyc:HS04039-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder	DIST64N5	Strong	Autosomal recessive	[1]
Cryptogenic multifocal ulcerous stenosing enteritis	DISPALDN	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Cytosolic phospholipase A2 (PLA2G4A) affects the response to substance of Fluorouracil.	[28]
acrolein	DMAMCSR	Investigative	Cytosolic phospholipase A2 (PLA2G4A) affects the response to substance of acrolein.	[29]

26 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 Cytosolic phospholipase A2 (PLA2G4A).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[15]
Ergotidine	DM78IME	Approved	Ergotidine increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[18]
Sodium chloride	DMM3950	Approved	Sodium chloride increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[19]
Budesonide	DMJIBAW	Approved	Budesonide decreases the activity of Cytosolic phospholipase A2 (PLA2G4A).	[20]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate decreases the activity of Cytosolic phospholipase A2 (PLA2G4A).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Cytosolic phospholipase A2 (PLA2G4A).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[11]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[26]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the expression of Cytosolic phospholipase A2 (PLA2G4A).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Capsaicin	DMGMF6V	Approved	Capsaicin increases the phosphorylation of Cytosolic phospholipase A2 (PLA2G4A).	[16]
Omeprazole	DM471KJ	Approved	Omeprazole increases the phosphorylation of Cytosolic phospholipase A2 (PLA2G4A).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluticasone propionate	DMRWLB2	Approved	Fluticasone propionate affects the localization of Cytosolic phospholipase A2 (PLA2G4A).	[21]

References

• [1] Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J Clin Invest. 2008 Jun;118(6):2121-31. doi: 10.1172/JCI30473.
• [2] Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-. Gut. 2014 Jan;63(1):96-104. doi: 10.1136/gutjnl-2012-303581. Epub 2012 Dec 25.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [10] 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.
• [11] 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.
• [12] Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain. Biol Psychiatry. 2004 Aug 15;56(4):248-54.
• [13] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [14] Troglitazone but not conjugated linoleic acid reduces gene expression and activity of matrix-metalloproteinases-2 and -9 in PMA-differentiated THP-1 macrophages. J Nutr Biochem. 2008 Sep;19(9):594-603. doi: 10.1016/j.jnutbio.2007.08.003. Epub 2007 Dec 21.
• [15] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [16] Signaling in TRPV1-induced platelet activating factor (PAF) in human esophageal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G233-40. doi: 10.1152/ajpgi.00409.2009. Epub 2009 Dec 3.
• [17] TCDD and omeprazole prime platelets through the aryl hydrocarbon receptor (AhR) non-genomic pathway. Toxicol Lett. 2015 May 19;235(1):28-36. doi: 10.1016/j.toxlet.2015.03.005. Epub 2015 Mar 19.
• [18] Leukotriene B4 mediates histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells. Am J Physiol. 1998 Jun;274(6):L1030-9.
• [19] Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells. Nanotoxicology. 2014 Aug;8(5):485-507.
• [20] Comparison of in vitro-activity of commonly used topical glucocorticoids on cytokine- and phospholipase inhibition. Eur J Med Res. 2004 Aug 31;9(8):383-90.
• [21] Glucocorticoid-induced surface expression of annexin 1 blocks beta2-integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein. J Allergy Clin Immunol. 2005 Mar;115(3):493-500. doi: 10.1016/j.jaci.2004.11.010.
• [22] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [23] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [24] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [25] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [26] 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.
• [27] Arachidonic acid, an omega-6 fatty acid, induces cytoplasmic phospholipase A2 in prostate carcinoma cells. Carcinogenesis. 2005 Sep;26(9):1520-6.
• [28] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [29] Genes Interacting with Occupational Exposures to Low Molecular Weight Agents and Irritants on Adult-Onset Asthma in Three European Studies. Environ Health Perspect. 2017 Feb;125(2):207-214. doi: 10.1289/EHP376. Epub 2016 Aug 9.