Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYERO80)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2)
• Synonyms: EC 3.1.4.11; Phosphoinositide phospholipase C-eta-2; Phosphoinositide phospholipase C-like 4; PLC-L4; Phospholipase C-like protein 4; Phospholipase C-eta-2; PLC-eta2
• Gene Name: PLCH2
• Related Disease:
  Schizophrenia
  Azoospermia
  Intellectual disability
• UniProt ID: PLCH2_HUMAN
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF09279 ; PF16457 ; PF00388 ; PF00387
• Sequence:
  MSGPWPSPDSRTKGTVAWLAEVLLWVGGSVVLSSEWQLGPLVERCMGAMQEGMQMVKLRG
  GSKGLVRFYYLDEHRSCIRWRPSRKNEKAKISIDSIQEVSEGRQSEVFQRYPDGSFDPNC
  CFSIYHGSHRESLDLVSTSSEVARTWVTGLRYLMAGISDEDSLARRQRTRDQWLKQTFDE
  ADKNGDGSLSIGEVLQLLHKLNVNLPRQRVKQMFREADTDDHQGTLGFEEFCAFYKMMST
  RRDLYLLMLTYSNHKDHLDAASLQRFLQVEQKMAGVTLESCQDIIEQFEPCPENKSKGLL
  GIDGFTNYTRSPAGDIFNPEHHHVHQDMTQPLSHYFITSSHNTYLVGDQLMSQSRVDMYA
  WVLQAGCRCVEVDCWDGPDGEPIVHHGYTLTSKILFKDVIETINKYAFIKNEYPVILSIE
  NHCSVIQQKKMAQYLTDILGDKLDLSSVSSEDATTLPSPQMLKGKILVKGKKLPANISED
  AEEGEVSDEDSADEIDDDCKLLNGDASTNRKRVENTAKRKLDSLIKESKIRDCEDPNNFS
  VSTLSPSGKLGRKSKAEEDVESGEDAGASRRNGRLVVGSFSRRKKKGSKLKKAASVEEGD
  EGQDSPGGQSRGATRQKKTMKLSRALSDLVKYTKSVATHDIEMEAASSWQVSSFSETKAH
  QILQQKPAQYLRFNQQQLSRIYPSSYRVDSSNYNPQPFWNAGCQMVALNYQSEGRMLQLN
  RAKFSANGGCGYVLKPGCMCQGVFNPNSEDPLPGQLKKQLVLRIISGQQLPKPRDSMLGD
  RGEIIDPFVEVEIIGLPVDCSREQTRVVDDNGFNPTWEETLVFMVHMPEIALVRFLVWDH
  DPIGRDFIGQRTLAFSSMMPGYRHVYLEGMEEASIFVHVAVSDISGKVKQALGLKGLFLR
  GPKPGSLDSHAAGRPPARPSVSQRILRRTASAPTKSQKPGRRGFPELVLGTRDTGSKGVA
  DDVVPPGPGPAPEAPAQEGPGSGSPRDTRPLSTQRPLPPLCSLETIAEEPAPGPGPPPPA
  AVPTSSSQGRPPYPTGPGANVASPLEDTEEPRDSRPRPCNGEGAGGAYERAPGSQTDGRS
  QPRTLGHLPVIRRVKSEGQVPTEPLGGWRPLAAPFPAPAVYSDATGSDPLWQRLEPCGHR
  DSVSSSSSMSSSDTVIDLSLPSLGLGRSRENLAGAHMGRLPPRPHSASAARPDLPPVTKS
  KSNPNLRATGQRPPIPDELQPRSLAPRMAGLPFRPPWGCLSLVGVQDCPVAAKSKSLGDL
  TADDFAPSFEGGSRRLSHSLGLPGGTRRVSGPGVRRDTLTEQLRWLTVFQQAGDITSPTS
  LGPAGEGVAGGPGFVRRSSSRSHSRVRAIASRARQAQERQQRLQGLGRQGPPEEERGTPE
  GACSVGHEGSVDAPAPSKGALGPASAAAENLVLLRL
• Function: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. This phospholipase activity is very sensitive to calcium. May be important for formation and maintenance of the neuronal network in the postnatal brain.
• Tissue Specificity: Expressed in retina and kidney.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]
Azoospermia	DIS94181	Limited	Genetic Variation	[2]
Intellectual disability	DISMBNXP	Limited	Biomarker	[3]

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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[6]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[7]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (PLCH2).	[10]

References

• [1] Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.JAMA Psychiatry. 2019 Oct 1;76(10):1026-1034. doi: 10.1001/jamapsychiatry.2019.1335.
• [2] A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia.Nat Genet. 2011 Dec 25;44(2):183-6. doi: 10.1038/ng.1040.
• [3] Role of phosphoinositide-specific phospholipase C 2 in isolated and syndromic mental retardation.Eur Neurol. 2011;65(5):264-9. doi: 10.1159/000327307. Epub 2011 Apr 8.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [8] 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.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.