Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSCYB9P)

• DOT Name: NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3)
• Synonyms: Complex I-9kD; CI-9kD; NADH-ubiquinone oxidoreductase 9 kDa subunit; Renal carcinoma antigen NY-REN-4
• Gene Name: NDUFV3
• Related Disease: Bipolar disorder
• UniProt ID: NDUV3_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF15880
• Sequence:
  MAAPCLLRQGRAGALKTMLQEAQVFRGLASTVSLSAESGKSEKGQPQNSKKQSPPKKPAP
  VPAEPFDNTTYKNLQHHDYSTYTFLDLNLELSKFRMPQPSSGRESPRH
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. May be the terminally assembled subunit of Complex I.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Complex I biogenesis (R-HSA-6799198)
  Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:HS08459-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
Bipolar disorder	DISAM7J2	Strong	Biomarker	[1]

11 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 NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of NADH dehydrogenase flavoprotein 3, mitochondrial (NDUFV3).	[12]

References

• [1] Isolation and characterization of a human chromosome 21q22.3 gene (WDR4) and its mouse homologue that code for a WD-repeat protein.Genomics. 2000 Aug 15;68(1):71-9. doi: 10.1006/geno.2000.6258.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Transcriptome responses in blood reveal distinct biological pathways associated with arsenic exposure through drinking water in rural settings of Punjab, Pakistan. Environ Int. 2020 Feb;135:105403. doi: 10.1016/j.envint.2019.105403. Epub 2019 Dec 18.
• [8] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [9] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [10] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [11] 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.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] 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.