Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX61TQQ)

• DOT Name: NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3)
• Synonyms: EC 7.1.1.2; Complex I-30kD; CI-30kD; NADH-ubiquinone oxidoreductase 30 kDa subunit
• Gene Name: NDUFS3
• Related Disease:
  Mitochondrial complex 1 deficiency, nuclear type 8
  Leigh syndrome
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: NDUS3_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF00329
• Sequence:
  MAAAAVARLWWRGILGASALTRGTGRPSVLLLPVRRESAGADTRPTVRPRNDVAHKQLSA
  FGEYVAEILPKYVQQVQVSCFNELEVCIHPDGVIPVLTFLRDHTNAQFKSLVDLTAVDVP
  TRQNRFEIVYNLLSLRFNSRIRVKTYTDELTPIESAVSVFKAANWYEREIWDMFGVFFAN
  HPDLRRILTDYGFEGHPFRKDFPLSGYVELRYDDEVKRVVAEPVELAQEFRKFDLNSPWE
  AFPVYRQPPESLKLEAGDKKPDAK
• Function: Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity and assembly 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)
  RHOG GTPase cycle (R-HSA-9013408)
  Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:G66-32694-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex 1 deficiency, nuclear type 8	DIS4P9LH	Strong	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[2]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[3]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[17]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of NADH dehydrogenase iron-sulfur protein 3, mitochondrial (NDUFS3).	[18]

References

• [1] Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet. 2004 Jan;41(1):14-7. doi: 10.1136/jmg.2003.014316.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet. 2012 Apr;49(4):277-83. doi: 10.1136/jmedgenet-2012-100846.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Arsenic modulates posttranslational S-nitrosylation and translational proteome in keratinocytes. ScientificWorldJournal. 2014;2014:360153.
• [11] The effects of quercetin on SW480 human colon carcinoma cells: a proteomic study. Nutr J. 2005 Mar 4;4:11.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [14] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [15] Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet. 2014 Apr 15;23(8):2106-19.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [18] PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicology. 2015 Aug 6;334:72-80.