Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8MUO5U)

• DOT Name: Cytosolic phospholipase A2 zeta (PLA2G4F)
• Synonyms: cPLA2-zeta; EC 3.1.1.4; Phospholipase A2 group IVF
• Gene Name: PLA2G4F
• Related Disease: Osteoarthritis
• UniProt ID: PA24F_HUMAN
• EC Number: 3.1.1.4
• Pfam ID: PF00168 ; PF18695 ; PF01735
• Sequence:
  MLWALWPRWLADKMLPLLGAVLLQKREKRGPLWRHWRRETYPYYDLQVKVLRATNIRGTD
  LLSKADCYVQLWLPTASPSPAQTRIVANCSDPEWNETFHYQIHGAVKNVLELTLYDKDIL
  GSDQLSLLLFDLRSLKCGQPHKHTFPLNHQDSQELQVEFVLEKSQVPASEVITNGVLVAH
  PCLRIQGTLRGDGTAPREEYGSRQLQLAVPGAYEKPQLLPLQPPTEPGLPPTFTFHVNPV
  LSSRLHVELMELLAAVQSGPSAELEAQTSKLGEGGILLSSLPLGQEEQCSVALGEGQEVA
  LSMKVEMSSGDLDLRLGFDLSDGEQEFLDRRKQVVSKALQQVLGLSEALDSGQVPVVAVL
  GSGGGTRAMSSLYGSLAGLQELGLLDTVTYLSGVSGSTWCISTLYRDPAWSQVALQGPIE
  RAQVHVCSSKMGALSTERLQYYTQELGVRERSGHSVSLIDLWGLLVEYLLYQEENPAKLS
  DQQEAVRQGQNPYPIYTSVNVRTNLSGEDFAEWCEFTPYEVGFPKYGAYVPTELFGSELF
  MGRLLQLQPEPRICYLQGMWGSAFATSLDEIFLKTAGSGLSFLEWYRGSVNITDDCQKPQ
  LHNPSRLRTRLLTPQGPFSQAVLDIFTSRFTSAQSFNFTRGLCLHKDYVAGREFVAWKDT
  HPDAFPNQLTPMRDCLYLVDGGFAINSPFPLALLPQRAVDLILSFDYSLEAPFEVLKMTE
  KYCLDRGIPFPSIEVGPEDMEEARECYLFAKAEDPRSPIVLHFPLVNRTFRTHLAPGVER
  QTAEEKAFGDFVINRPDTPYGMMNFTYEPQDFYRLVALSRYNVLNNVETLKCALQLALDR
  HQARERAGA
• Function: Has calcium-dependent phospholipase and lysophospholipase activities with a potential role in membrane lipid remodeling and biosynthesis of lipid mediators. 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. In myocardial mitochondria, plays a major role in arachidonate release that is metabolically channeled to the formation of cardioprotective eicosanoids, epoxyeicosatrienoates (EETs).
• Tissue Specificity: Expressed in myocardium (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 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)
  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
Osteoarthritis	DIS05URM	moderate	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cytosolic phospholipase A2 zeta (PLA2G4F).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cytosolic phospholipase A2 zeta (PLA2G4F).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cytosolic phospholipase A2 zeta (PLA2G4F).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cytosolic phospholipase A2 zeta (PLA2G4F).	[4]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytosolic phospholipase A2 zeta (PLA2G4F).	[6]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Cytosolic phospholipase A2 zeta (PLA2G4F).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cytosolic phospholipase A2 zeta (PLA2G4F).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Cytosolic phospholipase A2 zeta (PLA2G4F).	[9]

References

• [1] Identification of pathways and genes associated with synovitis in osteoarthritis using bioinformatics analyses.Sci Rep. 2018 Jul 3;8(1):10050. doi: 10.1038/s41598-018-28280-6.
• [2] 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.
• [3] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [5] 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.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.