Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB22A4J)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3)
• Synonyms: EC 3.1.4.11; Phosphoinositide phospholipase C-delta-3; Phospholipase C-delta-3; PLC-delta-3
• Gene Name: PLCD3
• Related Disease:
  Matthew-Wood syndrome
  Alcohol dependence
  Nasopharyngeal carcinoma
• UniProt ID: PLCD3_HUMAN
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF14788 ; PF00388 ; PF00387
• Sequence:
  MLCGRWRRCRRPPEEPPVAAQVAAQVAAPVALPSPPTPSDGGTKRPGLRALKKMGLTEDE
  DVRAMLRGSRLRKIRSRTWHKERLYRLQEDGLSVWFQRRIPRAPSQHIFFVQHIEAVREG
  HQSEGLRRFGGAFAPARCLTIAFKGRRKNLDLAAPTAEEAQRWVRGLTKLRARLDAMSQR
  ERLDHWIHSYLHRADSNQDSKMSFKEIKSLLRMVNVDMNDMYAYLLFKECDHSNNDRLEG
  AEIEEFLRRLLKRPELEEIFHQYSGEDRVLSAPELLEFLEDQGEEGATLARAQQLIQTYE
  LNETAKQHELMTLDGFMMYLLSPEGAALDNTHTCVFQDMNQPLAHYFISSSHNTYLTDSQ
  IGGPSSTEAYVRAFAQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVVQAVRDHAFT
  LSPYPVILSLENHCGLEQQAAMARHLCTILGDMLVTQALDSPNPEELPSPEQLKGRVLVK
  GKKLPAARSEDGRALSDREEEEEDDEEEEEEVEAAAQRRLAKQISPELSALAVYCHATRL
  RTLHPAPNAPQPCQVSSLSERKAKKLIREAGNSFVRHNARQLTRVYPLGLRMNSANYSPQ
  EMWNSGCQLVALNFQTPGYEMDLNAGRFLVNGQCGYVLKPACLRQPDSTFDPEYPGPPRT
  TLSIQVLTAQQLPKLNAEKPHSIVDPLVRIEIHGVPADCARQETDYVLNNGFNPRWGQTL
  QFQLRAPELALVRFVVEDYDATSPNDFVGQFTLPLSSLKQGYRHIHLLSKDGASLSPATL
  FIQIRIQRS
• Function: Hydrolyzes the phosphatidylinositol 4,5-bisphosphate (PIP2) to generate 2 second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG mediates the activation of protein kinase C (PKC), while IP3 releases Ca(2+) from intracellular stores. Essential for trophoblast and placental development. May participate in cytokinesis by hydrolyzing PIP2 at the cleavage furrow. Regulates neurite outgrowth through the inhibition of RhoA/Rho kinase signaling.
• Tissue Specificity: Present in corneal epithelial cells (at protein level).
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  Phosphatidylinositol sig.ling system (hsa04070)
  Thyroid hormone sig.ling pathway (hsa04919)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Shigellosis (hsa05131)
• 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
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	Limited	Altered Expression	[1]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[2]

10 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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[13]

3 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 delta-3 (PLCD3).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3).	[11]

References

• [1] Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms.Cancer Med. 2020 Feb;9(3):859-871. doi: 10.1002/cam4.2699. Epub 2019 Dec 6.
• [2] PLCD3, a flotillin2-interacting protein, is involved in proliferation, migration and invasion of nasopharyngeal carcinoma cells.Oncol Rep. 2018 Jan;39(1):45-52. doi: 10.3892/or.2017.6080. Epub 2017 Nov 6.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] 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.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.