Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMRW5U5)

• DOT Name: Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1)
• Synonyms: Inositol 1,4,5-trisphosphate receptor-associated cGMP kinase substrate; JAW1-related protein MRVI1; Protein MRVI1
• Gene Name: IRAG1
• UniProt ID: IRAG1_HUMAN
• Pfam ID: PF05781
• Sequence:
  MGMDLTCPFGISPACGAQASWSIFGADAAEVPGTRGHSQQEAAMPHIPEDEEPPGEPQAA
  QSPAGQGPPAAGVSCSPTPTIVLTGDATSPEGETDKNLANRVHSPHKRLSHRHLKVSTAS
  LTSVDPAGHIIDLVNDQLPDISISEEDKKKNLALLEEAKLVSERFLTRRGRKSRSSPGDS
  PSAVSPNLSPSASPTSSRSNSLTVPTPPGLDVCSGPPSPLPGAPPQQKGDEADVSSPHPG
  EPNVPKGLADRKQNDQRKVSQGRLAPRPPPVEKSKEIAIEQKENFDPLQYPETTPKGLAP
  VTNSSGKMALNSPQPGPVESELGKQLLKTGWEGSPLPRSPTQDAAGVGPPASQGRGPAGE
  PMGPEAGSKAELPPTVSRPPLLRGLSWDSGPEEPGPRLQKVLAKLPLAEEEKRFAGKAGG
  KLAKAPGLKDFQIQVQPVRMQKLTKLREEHILMRNQNLVGLKLPDLSEAAEQEKGLPSEL
  SPAIEEEESKSGLDVMPNISDVLLRKLRVHRSLPGSAPPLTEKEVENVFVQLSLAFRNDS
  YTLESRINQAERERNLTEENTEKELENFKASITSSASLWHHCEHRETYQKLLEDIAVLHR
  LAARLSSRAEVVGAVRQEKRMSKATEVMMQYVENLKRTYEKDHAELMEFKKLANQNSSRS
  CGPSEDGVPRTARSMSLTLGKNMPRRRVSVAVVPKFNALNLPGQTPSSSSIPSLPALSES
  PNGKGSLPVTSALPALLENGKTNGDPDCEASAPALTLSCLEELSQETKARMEEEAYSKGF
  QEGLKKTKELQDLKEEEEEQKSESPEEPEEVEETEEEEKGPRSSKLEELVHFLQVMYPKL
  CQHWQVIWMMAAVMLVLTVVLGLYNSYNSCAEQADGPLGRSTCSAAQRDSWWSSGLQHEQ
  PTEQ
• Function: Plays a role as NO/PRKG1-dependent regulator of IP3-induced calcium release; its phosphorylation by PRKG1 inhibits bradykinin and IP3-induced calcium release from intracellular stores. Recruits PRKG1 to the endoplasmic reticulum and may mediate the assembly of PRKG1 and ITPR1 in a macrocomplex. Involved in PRKG1 signaling cascade leading to inhibition of platelet activation and aggregation. Mediates also NO-dependent inhibition of calcium signaling in gastrointestinal smooth muscle contributing to NO-dependent relaxation.
• Tissue Specificity: Expressed in the colon, rectum, and cultured colonic smooth muscle. Detected in various cancer cell lines.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
• Reactome Pathway: cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DOT

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[1]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[6]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[7]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[11]

2 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 Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inositol 1,4,5-triphosphate receptor associated 1 (IRAG1).	[9]

References

• [1] 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.
• [2] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [3] 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.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [7] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [8] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [9] 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.
• [10] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.