Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9IOONQ)

• DOT Name: NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6)
• Synonyms: Complex I-13kD-A; CI-13kD-A; NADH-ubiquinone oxidoreductase 13 kDa-A subunit
• Gene Name: NDUFS6
• Related Disease:
  Mitochondrial disease
  Arteriosclerosis
  Leigh syndrome
  Mitochondrial complex 1 deficiency, nuclear type 9
  Schizophrenia
  Melanoma
  Obsolete mitochondrial complex I deficiency, nuclear type
  Mitochondrial complex I deficiency
  Cervical cancer
  Cardiomyopathy
  Cervical carcinoma
• UniProt ID: NDUS6_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF10276
• Sequence:
  MAAAMTFCRLLNRCGEAARSLPLGARCFGVRVSPTGEKVTHTGQVYDDKDYRRIRFVGRQ
  KEVNENFAIDLIAEQPVSEVETRVIACDGGGGALGHPKVYINLDKETKTGTCGYCGLQFR
  QHHH
• 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.
• 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:ENSG00000145494-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[3]
Mitochondrial complex 1 deficiency, nuclear type 9	DIS0RXHE	Strong	Autosomal recessive	[4]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	moderate	Altered Expression	[6]
Obsolete mitochondrial complex I deficiency, nuclear type	DISO3LL4	Moderate	Autosomal recessive	[7]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[7]
Cervical cancer	DISFSHPF	Disputed	Biomarker	[8]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[9]
Cervical carcinoma	DIST4S00	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6) affects the response to substance of Vinblastine.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[15]

6 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 NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of NADH dehydrogenase iron-sulfur protein 6, mitochondrial (NDUFS6).	[17]

References

• [1] 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.
• [2] Proteomic analysis of rat aorta during atherosclerosis induced by high cholesterol diet and injection of vitamin D3.Clin Exp Pharmacol Physiol. 2006 Apr;33(4):305-9. doi: 10.1111/j.1440-1681.2006.04366.x.
• [3] NDUFS6 related Leigh syndrome: a case report and review of the literature.J Hum Genet. 2019 Jul;64(7):637-645. doi: 10.1038/s10038-019-0594-4. Epub 2019 Apr 4.
• [4] Comparison of free amino acid pools in dental plaque fluid from monkeys (Macaca fascicularis) fed on high and low sugar diets. Arch Oral Biol. 1978;23(11):989-92. doi: 10.1016/0003-9969(78)90254-6.
• [5] Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis.J Neural Transm (Vienna). 2009 Mar;116(3):275-89. doi: 10.1007/s00702-008-0156-y. Epub 2008 Nov 26.
• [6] CD147 interacts with NDUFS6 in regulating mitochondrial complex I activity and the mitochondrial apoptotic pathway in human malignant melanoma cells.Curr Mol Med. 2014;14(10):1252-64. doi: 10.2174/1566524014666141202144601.
• [7] NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Invest. 2004 Sep;114(6):837-45. doi: 10.1172/JCI20683.
• [8] Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha.Mol Cancer. 2008 Jun 17;7:58. doi: 10.1186/1476-4598-7-58.
• [9] Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy.Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6165-70. doi: 10.1073/pnas.1113987109. Epub 2012 Apr 2.
• [10] 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.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [15] 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.
• [16] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [17] In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):216-24.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.