Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1YBBO0)

• DOT Name: NmrA-like family domain-containing protein 1 (NMRAL1)
• Gene Name: NMRAL1
• Related Disease: Breast carcinoma
• UniProt ID: NMRL1_HUMAN
• PDB ID: 2EXX; 2WM3; 2WMD; 3DXF; 3E5M
• Pfam ID: PF05368
• Sequence:
  MVDKKLVVVFGGTGAQGGSVARTLLEDGTFKVRVVTRNPRKKAAKELRLQGAEVVQGDQD
  DQVIMELALNGAYATFIVTNYWESCSQEQEVKQGKLLADLARRLGLHYVVYSGLENIKKL
  TAGRLAAAHFDGKGEVEEYFRDIGVPMTSVRLPCYFENLLSHFLPQKAPDGKSYLLSLPT
  GDVPMDGMSVSDLGPVVLSLLKMPEKYVGQNIGLSTCRHTAEEYAALLTKHTRKVVHDAK
  MTPEDYEKLGFPGARDLANMFRFYALRPDRDIELTLRLNPKALTLDQWLEQHKGDFNLL
• Function: Redox sensor protein. Undergoes restructuring and subcellular redistribution in response to changes in intracellular NADPH/NADP(+) levels. At low NADPH concentrations the protein is found mainly as a monomer, and binds argininosuccinate synthase (ASS1), the enzyme involved in nitric oxide synthesis. Association with ASS1 impairs its activity and reduces the production of nitric oxide, which subsecuently prevents apoptosis. Under normal NADPH concentrations, the protein is found as a dimer and hides the binding site for ASS1. The homodimer binds one molecule of NADPH. Has higher affinity for NADPH than for NADP(+). Binding to NADPH is necessary to form a stable dimer.
• Reactome Pathway: Urea cycle (R-HSA-70635)
• BioCyc Pathway: MetaCyc:ENSG00000153406-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]

10 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 NmrA-like family domain-containing protein 1 (NMRAL1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[2]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NmrA-like family domain-containing protein 1 (NMRAL1).	[10]

References

• [1] Cellular redox sensor HSCARG negatively regulates the translesion synthesis pathway and exacerbates mammary tumorigenesis.Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25624-25633. doi: 10.1073/pnas.1910250116. Epub 2019 Dec 3.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.