Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN2RVX8)

• DOT Name: Cytosolic phospholipase A2 epsilon (PLA2G4E)
• Synonyms: cPLA2-epsilon; EC 3.1.1.4; Calcium-dependent N-acyltransferase; Phospholipase A2 group IVE
• Gene Name: PLA2G4E
• Related Disease: Panic disorder
• UniProt ID: PA24E_HUMAN
• EC Number: 3.1.1.4
• Pfam ID: PF00168 ; PF18695 ; PF01735
• Sequence:
  MSLQASEGCPGLGTNVFVPQSPQTDEEGSRSGRSFSEFEDTQDLDTPGLPPFCPMAPWGS
  EEGLSPCHLLTVRVIRMKNVRQADMLSQTDCFVSLWLPTASQKKLRTRTISNCPNPEWNE
  SFNFQIQSRVKNVLELSVCDEDTVTPDDHLLTVLYDLTKLCFRKKTHVKFPLNPQGMEEL
  EVEFLLEESPSPPETLVTNGVLVSRQVSCLEVHAQSRRRRKREKMKDLLVMVNESFENTQ
  RVRPCLEPCCPTSACFQTAACFHYPKYFQSQVHVEVPKSHWSCGLCCRSRKKGPISQPLD
  CLSDGQVMTLPVGESYELHMKSTPCPETLDVRLGFSLCPAELEFLQKRKVVVAKALKQVL
  QLEEDLQEDEVPLIAIMATGGGTRSMTSMYGHLLGLQKLNLLDCASYITGLSGATWTMAT
  LYRDPDWSSKNLEPAIFEARRHVVKDKLPSLFPDQLRKFQEELRQRSQEGYRVTFTDFWG
  LLIETCLGDERNECKLSDQRAALSCGQNPLPIYLTINVKDDVSNQDFREWFEFSPYEVGL
  QKYGAFIPSELFGSEFFMGRLVKRIPESRICYMLGLWSSIFSLNLLDAWNLSHTSEEFFH
  RWTREKVQDIEDEPILPEIPKCDANILETTVVIPGSWLSNSFREILTHRSFVSEFHNFLS
  GLQLHTNYLQNGQFSRWKDTVLDGFPNQLTESANHLCLLDTAFFVNSSYPPLLRPERKAD
  LIIHLNYCAGSQTKPLKQTCEYCTVQNIPFPKYELPDENENLKECYLMENPQEPDAPIVT
  FFPLINDTFRKYKAPGVERSPEELEQGQVDIYGPKTPYATKELTYTEATFDKLVKLSEYN
  ILNNKDTLLQALRLAVEKKKRLKGQCPS
• Function: Calcium-dependent N-acyltransferase involved in the biosynthesis of N-acyl ethanolamines (NAEs) in the brain. Transfers the sn-1 fatty acyl chain of phosphatidylcholine (fatty acyl donor) to the amine group of phosphatidylethanolamine (fatty acyl acceptor) to generate N-acyl phosphatidylethanolamine (NAPE). Similarly can use plasmenylethanolamine as a fatty acyl acceptor to form N-acyl plasmenylethanolamine (N-Acyl-PlsEt). Both NAPE and N-Acyl-PlsEt can serve as precursors of bioactive NAEs like N-arachidonoyl phosphatidylethanolamine also called anandamide. Has weak phospholipase A2 and lysophospholipase activities. Regulates intracellular membrane trafficking that requires modulation of membrane curvature as it occurs by enrichment in lysophospholipids. Promotes tubule formation involved in clathrin-independent endocytotic trafficking and cargo recycling.
• 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 PS (R-HSA-1482801)
  Acyl chain remodelling of PE (R-HSA-1482839)
  Acyl chain remodelling of PI (R-HSA-1482922)
  Hydrolysis of LPC (R-HSA-1483115)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Panic disorder	DISD3VNY	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytosolic phospholipase A2 epsilon (PLA2G4E).	[2]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytosolic phospholipase A2 epsilon (PLA2G4E).	[4]

1 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 increases the methylation of Cytosolic phospholipase A2 epsilon (PLA2G4E).	[3]

References

• [1] Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder.Transl Psychiatry. 2018 Feb 2;8(1):41. doi: 10.1038/s41398-017-0088-0.
• [2] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [3] 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.
• [4] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.