Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO9JO9U)

• DOT Name: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A)
• Synonyms: EC 2.7.1.149; 1-phosphatidylinositol 5-phosphate 4-kinase 2-alpha; Diphosphoinositide kinase 2-alpha; PIP5KIII; Phosphatidylinositol 5-Phosphate 4-Kinase; PI5P4Kalpha; Phosphatidylinositol 5-phosphate 4-kinase type II alpha; PI(5)P 4-kinase type II alpha; PIP4KII-alpha; PtdIns(4)P-5-kinase B isoform; PtdIns(4)P-5-kinase C isoform; PtdIns(5)P-4-kinase isoform 2-alpha
• Gene Name: PIP4K2A
• Related Disease:
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Adult glioblastoma
  Breast carcinoma
  Childhood acute lymphoblastic leukemia
  Glioblastoma multiforme
  leukaemia
  Leukemia
  Melanoma
  Mental disorder
  Myelodysplastic syndrome
  Neoplasm
  Burkitt lymphoma
  Lysosomal storage disease
  Myeloid neoplasm
• UniProt ID: PI42A_HUMAN
• PDB ID: 2YBX; 6OSP; 6UX9; 6YM3; 6YM4; 6YM5; 7N6Z; 7N71; 7N7J; 7N7K; 7N7L; 7N7M; 7N7N; 7N7O; 8C8C
• EC Number: 2.7.1.149
• Pfam ID: PF01504
• Sequence:
  MATPGNLGSSVLASKTKTKKKHFVAQKVKLFRASDPLLSVLMWGVNHSINELSHVQIPVM
  LMPDDFKAYSKIKVDNHLFNKENMPSHFKFKEYCPMVFRNLRERFGIDDQDFQNSLTRSA
  PLPNDSQARSGARFHTSYDKRYIIKTITSEDVAEMHNILKKYHQYIVECHGITLLPQFLG
  MYRLNVDGVEIYVIVTRNVFSHRLSVYRKYDLKGSTVAREASDKEKAKELPTLKDNDFIN
  EGQKIYIDDNNKKVFLEKLKKDVEFLAQLKLMDYSLLVGIHDVERAEQEEVECEENDGEE
  EGESDGTHPVGTPPDSPGNTLNSSPPLAPGEFDPNIDVYGIKCHENSPRKEVYFMAIIDI
  LTHYDAKKKAAHAAKTVKHGAGAEISTVNPEQYSKRFLDFIGHILT
• Function: Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Has both ATP- and GTP-dependent kinase activities. May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2. May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation. Required for lysosome-peroxisome membrane contacts and intracellular cholesterol transport through modulating peroxisomal PtdIns(4,5)P2 level. In collaboration with PIP4K2B, has a role in mediating autophagy in times of nutrient stress. Required for autophagosome-lysosome fusion and the regulation of cellular lipid metabolism. May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size. Negatively regulates insulin signaling through a catalytic-independent mechanism. PIP4Ks interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3.
• Tissue Specificity: Expressed ubiquitously, with high levels in the brain. Present in most tissues, except notably skeletal muscle and small intestine.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  PI5P Regulates TP53 Acetylation (R-HSA-6811555)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Synthesis of PIPs in the nucleus (R-HSA-8847453)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS07693-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
leukaemia	DISS7D1V	Strong	Biomarker	[6]
Leukemia	DISNAKFL	Strong	Biomarker	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[7]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[8]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[10]
Burkitt lymphoma	DIS9D5XU	moderate	SusceptibilityMutation	[10]
Lysosomal storage disease	DIS6QM6U	Limited	Altered Expression	[11]
Myeloid neoplasm	DIS2YOWO	Limited	Biomarker	[12]

15 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 Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[22]
Marinol	DM70IK5	Approved	Marinol increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[23]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[24]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[25]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A).	[29]

References

• [1] Association Between PIP4K2A Polymorphisms and Acute Lymphoblastic Leukemia Susceptibility.Medicine (Baltimore). 2016 May;95(18):e3542. doi: 10.1097/MD.0000000000003542.
• [2] PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia.Cancer Genet. 2019 Apr;233-234:56-66. doi: 10.1016/j.cancergen.2019.04.002. Epub 2019 Apr 11.
• [3] PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma.J Exp Med. 2019 May 6;216(5):1120-1134. doi: 10.1084/jem.20172170. Epub 2019 Mar 21.
• [4] Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma.Oncol Lett. 2017 Jan;13(1):488-496. doi: 10.3892/ol.2016.5438. Epub 2016 Nov 28.
• [5] BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.Int J Cancer. 2018 Dec 1;143(11):2647-2658. doi: 10.1002/ijc.31622. Epub 2018 Oct 3.
• [6] Regulatory Network and Prognostic Effect Investigation of PIP4K2A in Leukemia and Solid Cancers.Front Genet. 2019 Jan 15;9:721. doi: 10.3389/fgene.2018.00721. eCollection 2018.
• [7] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [8] Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.Am J Med Genet B Neuropsychiatr Genet. 2003 Nov 15;123B(1):50-8. doi: 10.1002/ajmg.b.20012.
• [9] Differential profile of PIP4K2A expression in hematological malignancies.Blood Cells Mol Dis. 2015 Oct;55(3):228-35. doi: 10.1016/j.bcmd.2015.06.014. Epub 2015 Jun 30.
• [10] Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype.Blood. 2013 Nov 7;122(19):3298-307. doi: 10.1182/blood-2013-03-491316. Epub 2013 Aug 30.
• [11] PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P(2) homeostasis.J Lipid Res. 2018 Mar;59(3):507-514. doi: 10.1194/jlr.M082149. Epub 2018 Jan 20.
• [12] A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.Oncogene. 2015 Mar 5;34(10):1253-1262. doi: 10.1038/onc.2014.77. Epub 2014 Mar 31.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] 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.
• [21] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [22] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [23] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [24] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [25] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.