Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTWC00K)

• DOT Name: Phosphatidylinositol transfer protein alpha isoform (PITPNA)
• Synonyms: PI-TP-alpha; PtdIns transfer protein alpha; PtdInsTP alpha
• Gene Name: PITPNA
• Related Disease:
  Chronic obstructive pulmonary disease
  Chylomicron retention disease
  Duchenne muscular dystrophy
  Metastatic malignant neoplasm
• UniProt ID: PIPNA_HUMAN
• PDB ID: 1UW5
• Pfam ID: PF02121
• Sequence:
  MVLLKEYRVILPVSVDEYQVGQLYSVAEASKNETGGGEGVEVLVNEPYEKDGEKGQYTHK
  IYHLQSKVPTFVRMLAPEGALNIHEKAWNAYPYCRTVITNEYMKEDFLIKIETWHKPDLG
  TQENVHKLEPEAWKHVEAVYIDIADRSQVLSKDYKAEEDPAKFKSIKTGRGPLGPNWKQE
  LVNQKDCPYMCAYKLVTVKFKWWGLQNKVENFIHKQERRLFTNFHRQLFCWLDKWVDLTM
  DDIRRMEEETKRQLDEMRQKDPVKGMTADD
• Function: Catalyzes the transfer of phosphatidylinositol (PI) and phosphatidylcholine (PC) between membranes. Shows a preference for PI and PC containing shorter saturated or monosaturated acyl chains at the sn-1 and sn-2 positions. Preference order for PC is C16:1 > C16:0 > C18:1 > C18:0 > C20:4 and for PI is C16:1 > C16:0 > C18:1 > C18:0 > C20:4 > C20:3.
• Reactome Pathway:
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Role of second messengers in netrin-1 signaling (R-HSA-418890)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[1]
Chylomicron retention disease	DISOUTV5	Strong	Biomarker	[2]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[4]

12 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 transfer protein alpha isoform (PITPNA).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[16]

1 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 affects the methylation of Phosphatidylinositol transfer protein alpha isoform (PITPNA).	[12]

References

• [1] A genome-wide analysis of the response to inhaled 2-agonists in chronic obstructive pulmonary disease.Pharmacogenomics J. 2016 Aug;16(4):326-35. doi: 10.1038/tpj.2015.65. Epub 2015 Oct 27.
• [2] Mice lacking phosphatidylinositol transfer protein-alpha exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia.J Biol Chem. 2003 Aug 29;278(35):33501-18. doi: 10.1074/jbc.M303591200. Epub 2003 Jun 4.
• [3] Repression of phosphatidylinositol transfer protein ameliorates the pathology of Duchenne muscular dystrophy.Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):6080-6085. doi: 10.1073/pnas.1703556114. Epub 2017 May 22.
• [4] Phosphatidylinositol transfer protein- in platelets is inconsequential for thrombosis yet is utilized for tumor metastasis.Nat Commun. 2017 Oct 31;8(1):1216. doi: 10.1038/s41467-017-01181-4.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [8] 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.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] 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.
• [13] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.