Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ2MEFA)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCZ1)
• Synonyms: EC 3.1.4.11; Phosphoinositide phospholipase C-zeta-1; Phospholipase C-zeta-1; PLC-zeta-1; Testis-development protein NYD-SP27
• Gene Name: PLCZ1
• Related Disease:
  Cystic fibrosis
  Male infertility
  Ovarian neoplasm
  Spermatogenic failure 17
• UniProt ID: PLCZ1_HUMAN
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF09279 ; PF00388 ; PF00387
• Sequence:
  MEMRWFLSKIQDDFRGGKINLEKTQRLLEKLDIRCSYIHVKQIFKDNDRLKQGRITIEEF
  RAIYRIITHREEIIEIFNTYSENRKILLASNLAQFLTQEQYAAEMSKAIAFEIIQKYEPI
  EEVRKAHQMSLEGFTRYMDSRECLLFKNECRKVYQDMTHPLNDYFISSSHNTYLVSDQLL
  GPSDLWGYVSALVKGCRCLEIDCWDGAQNEPVVYHGYTLTSKLLFKTVIQAIHKYAFMTS
  DYPVVLSLENHCSTAQQEVMADNLQATFGESLLSDMLDDFPDTLPSPEALKFKILVKNKK
  IGTLKETHERKGSDKRGDNQDKETGVKKLPGVMLFKKKKTRKLKIALALSDLVIYTKAEK
  FKSFQHSRLYQQFNENNSIGETQARKLSKLRVHEFIFHTRKFITRIYPKATRADSSNFNP
  QEFWNIGCQMVALNFQTPGLPMDLQNGKFLDNGGSGYILKPHFLRESKSYFNPSNIKEGM
  PITLTIRLISGIQLPLTHSSSNKGDSLVIIEVFGVPNDQMKQQTRVIKKNAFSPRWNETF
  TFIIHVPELALIRFVVEGQGLIAGNEFLGQYTLPLLCMNKGYRRIPLFSRMGESLEPASL
  FVYVWYVR
• 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. In vitro, hydrolyzes PtdIns(4,5)P2 in a Ca(2+)-dependent manner. Triggers intracellular Ca(2+) oscillations in oocytes solely during M phase and is involved in inducing oocyte activation and initiating embryonic development up to the blastocyst stage. Is therefore a strong candidate for the egg-activating soluble sperm factor that is transferred from the sperm into the egg cytoplasm following gamete membrane fusion. May exert an inhibitory effect on phospholipase-C-coupled processes that depend on calcium ions and protein kinase C, including CFTR trafficking and function.
• Tissue Specificity: Expressed specifically in testis and sperm. Weakly expressed in pancreatic-duct cells. Up-regulated in pancreatic-duct cells from patients with cystic fibrosis.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  Phosphatidylinositol sig.ling system (hsa04070)
  Oocyte meiosis (hsa04114)
  Thyroid hormone sig.ling pathway (hsa04919)
  Shigellosis (hsa05131)
• Reactome Pathway: Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[1]
Male infertility	DISY3YZZ	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[3]
Spermatogenic failure 17	DIS6VKD0	Strong	Autosomal recessive	[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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCZ1).	[5]

References

• [1] Rescue of defective pancreatic secretion in cystic-fibrosis cells by suppression of a novel isoform of phospholipase C.Lancet. 2003 Dec 20;362(9401):2059-65. doi: 10.1016/s0140-6736(03)15100-8.
• [2] A maternally inherited autosomal point mutation in human phospholipase C zeta (PLC) leads to male infertility.Hum Reprod. 2012 Jan;27(1):222-31. doi: 10.1093/humrep/der384. Epub 2011 Nov 16.
• [3] Broad, ectopic expression of the sperm protein PLCZ1 induces parthenogenesis and ovarian tumours in mice.Development. 2007 Nov;134(21):3941-52. doi: 10.1242/dev.007930.
• [4] Reduced amounts and abnormal forms of phospholipase C zeta (PLCzeta) in spermatozoa from infertile men. Hum Reprod. 2009 Oct;24(10):2417-28. doi: 10.1093/humrep/dep207. Epub 2009 Jul 7.
• [5] 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.