Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT14EZVB)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4)
• Synonyms: hPLCD4; EC 3.1.4.11; Phosphoinositide phospholipase C-delta-4; Phospholipase C-delta-4; PLC-delta-4
• Gene Name: PLCD4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Pulmonary arterial hypertension
• UniProt ID: PLCD4_HUMAN
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF13202 ; PF09279 ; PF00169 ; PF00388 ; PF00387
• Sequence:
  MASLLQDQLTTDQDLLLMQEGMPMRKVRSKSWKKLRYFRLQNDGMTVWHARQARGSAKPS
  FSISDVETIRNGHDSELLRSLAEELPLEQGFTIVFHGRRSNLDLMANSVEEAQIWMRGLQ
  LLVDLVTSMDHQERLDQWLSDWFQRGDKNQDGKMSFQEVQRLLHLMNVEMDQEYAFSLFQ
  AADTSQSGTLEGEEFVQFYKALTKRAEVQELFESFSADGQKLTLLEFLDFLQEEQKERDC
  TSELALELIDRYEPSDSGKLRHVLSMDGFLSYLCSKDGDIFNPACLPIYQDMTQPLNHYF
  ICSSHNTYLVGDQLCGQSSVEGYIRALKRGCRCVEVDVWDGPSGEPVVYHGHTLTSRILF
  KDVVATVAQYAFQTSDYPVILSLETHCSWEQQQTMARHLTEILGEQLLSTTLDGVLPTQL
  PSPEELRRKILVKGKKLTLEEDLEYEEEEAEPELEESELALESQFETEPEPQEQNLQNKD
  KKKKSKPILCPALSSLVIYLKSVSFRSFTHSKEHYHFYEISSFSETKAKRLIKEAGNEFV
  QHNTWQLSRVYPSGLRTDSSNYNPQELWNAGCQMVAMNMQTAGLEMDICDGHFRQNGGCG
  YVLKPDFLRDIQSSFHPEKPISPFKAQTLLIQVISGQQLPKVDKTKEGSIVDPLVKVQIF
  GVRLDTARQETNYVENNGFNPYWGQTLCFRVLVPELAMLRFVVMDYDWKSRNDFIGQYTL
  PWTCMQQGYRHIHLLSKDGISLRPASIFVYICIQEGLEGDES
• 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. Required for acrosome reaction in sperm during fertilization, probably by acting as an important enzyme for intracellular Ca(2+) mobilization in the zona pellucida-induced acrosome reaction. May play a role in cell growth. Modulates the liver regeneration in cooperation with nuclear PKC. Overexpression up-regulates the Erk signaling pathway and proliferation; [Isoform 2]: Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates guanine nucleotide-binding protein (G-protein) alpha subunit GNAI3.
• Tissue Specificity: Highly expressed in skeletal muscle and kidney tissues, and at moderate level in intestinal tissue. Expressed in corneal epithelial cells.
• 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
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4).	[4]

2 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-4 (PLCD4).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4).	[6]

References

• [1] Phospholipase C delta-4 overexpression upregulates ErbB1/2 expression, Erk signaling pathway, and proliferation in MCF-7 cells.Mol Cancer. 2004 May 13;3:15. doi: 10.1186/1476-4598-3-15.
• [2] The P2-receptor-mediated Ca(2+) signalosome of the human pulmonary endothelium - implications for pulmonary arterial hypertension.Purinergic Signal. 2019 Sep;15(3):299-311. doi: 10.1007/s11302-019-09674-1. Epub 2019 Aug 8.
• [3] 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.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [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.
• [6] 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.