Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0D51QP)

• DOT Name: Phosphatidylinositol 4-kinase type 2-beta (PI4K2B)
• Synonyms: EC 2.7.1.67; Phosphatidylinositol 4-kinase type II-beta; PI4KII-BETA
• Gene Name: PI4K2B
• Related Disease:
  Attention deficit hyperactivity disorder
  leukaemia
  Leukemia
  Mental disorder
• UniProt ID: P4K2B_HUMAN
• PDB ID: 4WTV; 8A5X
• EC Number: 2.7.1.67
• Pfam ID: PF00454
• Sequence:
  MEDPSEPDRLASADGGSPEEEEDGEREPLLPRIAWAHPRRGAPGSAVRLLDAAGEEGEAG
  DEELPLPPGDVGVSRSSSAELDRSRPAVSVTIGTSEMNAFLDDPEFADIMLRAEQAIEVG
  IFPERISQGSSGSYFVKDPKRKIIGVFKPKSEEPYGQLNPKWTKYVHKVCCPCCFGRGCL
  IPNQGYLSEAGAYLVDNKLHLSIVPKTKVVWLVSETFNYNAIDRAKSRGKKYALEKVPKV
  GRKFHRIGLPPKIGSFQLFVEGYKEAEYWLRKFEADPLPENIRKQFQSQFERLVILDYII
  RNTDRGNDNWLVRYEKQKCEKEIDHKESKWIDDEEFLIKIAAIDNGLAFPFKHPDEWRAY
  PFHWAWLPQAKVPFSEEIRNLILPYISDMNFVQDLCEDLYELFKTDKGFDKATFESQMSV
  MRGQILNLTQALRDGKSPFQLVQIPCVIVERSQGGSQGRIVHLSNSFTQTVNCRKPFFSS
  W
• Function: Together with PI4K2A and the type III PI4Ks (PIK4CA and PIK4CB) it contributes to the overall PI4-kinase activity of the cell. This contribution may be especially significant in plasma membrane, endosomal and Golgi compartments. The phosphorylation of phosphatidylinositol (PI) to PI4P is the first committed step in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2), a precursor of the second messenger inositol 1,4,5-trisphosphate (InsP3). Contributes to the production of InsP3 in stimulated cells and is likely to be involved in the regulation of vesicular trafficking.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Synthesis of PIPs at the early endosome membrane (R-HSA-1660516)
  Synthesis of PIPs at the ER membrane (R-HSA-1483248)
• BioCyc Pathway: MetaCyc:HS00529-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[1]
leukaemia	DISS7D1V	Strong	Biomarker	[2]
Leukemia	DISNAKFL	Strong	Biomarker	[2]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[3]

9 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 4-kinase type 2-beta (PI4K2B).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylinositol 4-kinase type 2-beta (PI4K2B).	[15]

References

• [1] A case-control genome-wide association study of ADHD discovers a novel association with the tenascin R (TNR) gene.Transl Psychiatry. 2018 Dec 18;8(1):284. doi: 10.1038/s41398-018-0329-x.
• [2] Identification of phosphatidylinositol 4-kinase type II beta as HLA class II-restricted target in graft versus leukemia reactivity.Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3837-42. doi: 10.1073/pnas.0712250105. Epub 2008 Mar 3.
• [3] A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B.J Psychiatr Res. 2009 Dec;43(16):1272-7. doi: 10.1016/j.jpsychires.2009.05.004. Epub 2009 Jun 17.
• [4] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] 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.
• [15] 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.