Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT991XS0)

• DOT Name: Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1)
• Synonyms: Type 1 PtdIns-4,5-P2 4-Ptase; EC 3.1.3.78; PtdIns-4,5-P2 4-Ptase I; Transmembrane protein 55B
• Gene Name: PIP4P1
• UniProt ID: PP4P1_HUMAN
• PDB ID: 8OQH
• EC Number: 3.1.3.78
• Pfam ID: PF09788
• Sequence:
  MAADGERSPLLSEPIDGGAGGNGLVGPGGSGAGPGGGLTPSAPPYGAAFPPFPEGHPAVL
  PGEDPPPYSPLTSPDSGSAPMITCRVCQSLINVEGKMHQHVVKCGVCNEATPIKNAPPGK
  KYVRCPCNCLLICKVTSQRIACPRPYCKRIINLGPVHPGPLSPEPQPMGVRVICGHCKNT
  FLWTEFTDRTLARCPHCRKVSSIGRRYPRKRCICCFLLGLLLAVTATGLAFGTWKHARRY
  GGIYAAWAFVILLAVLCLGRALYWACMKVSHPVQNFS
• 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. Regulates lysosomal positioning by recruiting JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules. Contributes to assembly of the V-ATPase complex in lipid rafts of the lysosomal membrane and to subsequent amino acid-dependent activation of mTORC1. May play a role in the regulation of cellular cholesterol metabolism.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Synthesis of PIPs in the nucleus (R-HSA-8847453)
  PI5P Regulates TP53 Acetylation (R-HSA-6811555)
• BioCyc Pathway: MetaCyc:HS15363-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 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 Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[7]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1).	[12]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] 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.
• [6] 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.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] 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.