Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8OVB6R)

• DOT Name: Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2)
• Synonyms: Type 2 PtdIns-4,5-P2 4-Ptase; EC 3.1.3.78; PtdIns-4,5-P2 4-Ptase II; Transmembrane protein 55A
• Gene Name: PIP4P2
• Related Disease: Parkinson disease
• UniProt ID: PP4P2_HUMAN
• EC Number: 3.1.3.78
• Pfam ID: PF09788
• Sequence:
  MAADGVDERSPLLSASHSGNVTPTAPPYLQESSPRAELPPPYTAIASPDASGIPVINCRV
  CQSLINLDGKLHQHVVKCTVCNEATPIKNPPTGKKYVRCPCNCLLICKDTSRRIGCPRPN
  CRRIINLGPVMLISEEQPAQPALPIQPEGTRVVCGHCGNTFLWMELRFNTLAKCPHCKKI
  SSVGSALPRRRCCAYITIGMICIFIGVGLTVGTPDFARRFRATYVSWAIAYLLGLICLIR
  ACYWGAIRVSYPEHSFA
• Function: Catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P). Does not hydrolyze phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-bisphosphate, inositol 3,5-bisphosphate, inositol 3,4-bisphosphate, phosphatidylinositol 5-monophosphate, phosphatidylinositol 4-monophosphate and phosphatidylinositol 3-monophosphate. Negatively regulates the phagocytosis of large particles by reducing phagosomal phosphatidylinositol 4,5-bisphosphate accumulation during cup formation.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Phosphatidylinositol sig.ling system (hsa04070)
• BioCyc Pathway: MetaCyc:HS14553-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P2).	[14]

References

• [1] Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data.Lancet Neurol. 2006 Nov;5(11):911-6. doi: 10.1016/S1474-4422(06)70578-6.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] 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.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.