Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ34981)

• DOT Name: Nodal homolog (NODAL)
• Gene Name: NODAL
• Related Disease:
  Situs inversus
  Heterotaxy, visceral, 5, autosomal
• UniProt ID: NODAL_HUMAN
• PDB ID: 4N1D
• Pfam ID: PF00019
• Sequence:
  MHAHCLPFLLHAWWALLQAGAATVATALLRTRGQPSSPSPLAYMLSLYRDPLPRADIIRS
  LQAEDVAVDGQNWTFAFDFSFLSQQEDLAWAELRLQLSSPVDLPTEGSLAIEIFHQPKPD
  TEQASDSCLERFQMDLFTVTLSQVTFSLGSMVLEVTRPLSKWLKHPGALEKQMSRVAGEC
  WPRPPTPPATNVLLMLYSNLSQEQRQLGGSTLLWEAESSWRAQEGQLSWEWGKRHRRHHL
  PDRSQLCRKVKFQVDFNLIGWGSWIIYPKQYNAYRCEGECPNPVGEEFHPTNHAYIQSLL
  KRYQPHRVPSTCCAPVKTKPLSMLYVDNGRVLLDHHKDMIVEECGCL
• Function: Essential for mesoderm formation and axial patterning during embryonic development.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Regulation of signaling by NODAL (R-HSA-1433617)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Situs inversus	DISFA7AJ	Definitive	Autosomal dominant	[1]
Heterotaxy, visceral, 5, autosomal	DIS3D4CH	Strong	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Nodal homolog (NODAL).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Nodal homolog (NODAL).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nodal homolog (NODAL).	[5]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Nodal homolog (NODAL).	[6]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Nodal homolog (NODAL).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nodal homolog (NODAL).	[9]

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 increases the methylation of Nodal homolog (NODAL).	[7]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet. 2009 Mar 1;18(5):861-71. doi: 10.1093/hmg/ddn411. Epub 2008 Dec 8.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [5] MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance. J Cell Sci. 2011 Feb 1;124(Pt 3):359-68. doi: 10.1242/jcs.072223. Epub 2011 Jan 11.
• [6] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [7] 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.
• [8] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [9] Unique bisphenol A transcriptome in prostate cancer: novel effects on ERbeta expression that correspond to androgen receptor mutation status. Environ Health Perspect. 2007 Nov;115(11):1646-53. doi: 10.1289/ehp.10283.