Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQXF4FF)

• DOT Name: Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2)
• Synonyms: Phosphatidylinositol transfer protein, membrane-associated 2; PITPnm 2; Pyk2 N-terminal domain-interacting receptor 3; NIR-3
• Gene Name: PITPNM2
• Related Disease:
  Multiple sclerosis
  Non-insulin dependent diabetes
  Schizophrenia
• UniProt ID: PITM2_HUMAN
• Pfam ID: PF02862 ; PF02121
• Sequence:
  MIIKEYRIPLPMTVEEYRIAQLYMIQKKSRNETYGEGSGVEILENRPYTDGPGGSGQYTH
  KVYHVGMHIPSWFRSILPKAALRVVEESWNAYPYTRTRFTCPFVEKFSIDIETFYKTDAG
  ENPDVFNLSPVEKNQLTIDFIDIVKDPVPHNEYKTEEDPKLFQSTKTQRGPLSENWIEEY
  KKQVFPIMCAYKLCKVEFRYWGMQSKIERFIHDTGLRRVMVRAHRQAWCWQDEWYGLSME
  NIRELEKEAQLMLSRKMAQFNEDGEEATELVKHEAVSDQTSGEPPEPSSSNGEPLVGRGL
  KKQWSTSSKSSRSSKRGASPSRHSISEWRMQSIARDSDESSDDEFFDAHEDLSDTEEMFP
  KDITKWSSNDLMDKIESPEPEDTQDGLYRQGAPEFRVASSVEQLNIIEDEVSQPLAAPPS
  KIHVLLLVLHGGTILDTGAGDPSSKKGDANTIANVFDTVMRVHYPSALGRLAIRLVPCPP
  VCSDAFALVSNLSPYSHDEGCLSSSQDHIPLAALPLLATSSPQYQEAVATVIQRANLAYG
  DFIKSQEGMTFNGQVCLIGDCVGGILAFDALCYSNQPVSESQSSSRRGSVVSMQDNDLLS
  PGILMNAAHCCGGGGGGGGGGGSSGGGGSSGGSSLESSRHLSRSNVDIPRSNGTEDPKRQ
  LPRKRSDSSTYELDTIQQHQAFLSSLHASVLRTEPCSRHSSSSTMLDGTGALGRFDFEIT
  DLFLFGCPLGLVLALRKTVIPALDVFQLRPACQQVYNLFHPADPSASRLEPLLERRFHAL
  PPFSVPRYQRYPLGDGCSTLLADVLQTHNAAFQEHGAPSSPGTAPASRGFRRASEISIAS
  QVSGMAESYTASSIAQKAPDALSHTPSVRRLSLLALPAPSPTTPGPHPPARKASPGLERA
  PGLPELDIGEVAAKWWGQKRIDYALYCPDALTAFPTVALPHLFHASYWESTDVVSFLLRQ
  VMRHDNSSILELDGKEVSVFTPSKPREKWQRKRTHVKLRNVTANHRINDALANEDGPQVL
  TGRFMYGPLDMVTLTGEKVDVHIMTQPPSGEWLYLDTLVTNNSGRVSYTIPESHRLGVGV
  YPIKMVVRGDHTFADSYITVLPKGTEFVVFSIDGSFAASVSIMGSDPKVRAGAVDVVRHW
  QDLGYLIIYVTGRPDMQKQRVVAWLAQHNFPHGVVSFCDGLVHDPLRHKANFLKLLISEL
  HLRVHAAYGSTKDVAVYSAISLSPMQIYIVGRPTKKLQQQCQFITDGYAAHLAQLKYSHR
  ARPARNTATRMALRKGSFGLPGQGDFLRSRNHLLRTISAQPSGPSHRHERTQSQADGEQR
  GQRSMSVAAGCWGRAMTGRLEPGAAAGPK
• Function: Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro). Binds calcium ions.
• Tissue Specificity: Highly expressed in brain, heart, ovary, testis and thymus. Detected in small intestine, prostate, pancreas, skeletal muscle, liver, colon and placenta.
• Reactome Pathway: Synthesis of PI (R-HSA-1483226)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[12]

8 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 Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Membrane-associated phosphatidylinositol transfer protein 2 (PITPNM2).	[14]

References

• [1] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [2] Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.Nat Commun. 2018 Jul 27;9(1):2941. doi: 10.1038/s41467-018-04951-w.
• [3] Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.JAMA Psychiatry. 2019 Oct 1;76(10):1026-1034. doi: 10.1001/jamapsychiatry.2019.1335.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] 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.