Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIXNT91)

• DOT Name: NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6)
• Synonyms: Complex I-B17; CI-B17; NADH-ubiquinone oxidoreductase B17 subunit
• Gene Name: NDUFB6
• Related Disease:
  Clear cell renal carcinoma
  Neoplasm
  Acute myelogenous leukaemia
  Gastric cancer
  Stomach cancer
  Obesity
• UniProt ID: NDUB6_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF09782
• Sequence:
  MTGYTPDEKLRLQQLRELRRRWLKDQELSPREPVLPPQKMGPMEKFWNKFLENKSPWRKM
  VHGVYKKSIFVFTHVLVPVWIIHYYMKYHVSEKPYGIVEKKSRIFPGDTILETGEVIPPM
  KEFPDQHH
• 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:HS09208-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[2]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[3]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[3]
Obesity	DIS47Y1K	Limited	Biomarker	[4]

16 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 NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[14]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[21]

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 decreases the methylation of NADH dehydrogenase 1 beta subcomplex subunit 6 (NDUFB6).	[16]

References

• [1] Downregulation of NDUFB6 due to 9p24.1-p13.3 loss is implicated in metastatic clear cell renal cell carcinoma.Cancer Med. 2015 Jan;4(1):112-24. doi: 10.1002/cam4.351. Epub 2014 Oct 15.
• [2] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [3] Identification and functional annotation of metabolism-associated lncRNAs and their related protein-coding genes in gastric cancer.Mol Genet Genomic Med. 2018 Sep;6(5):728-738. doi: 10.1002/mgg3.427. Epub 2018 Jul 10.
• [4] A high-sucrose isocaloric pair-fed model induces obesity and impairs NDUFB6 gene function in rat adipose tissue.J Nutrigenet Nutrigenomics. 2009;2(6):267-72. doi: 10.1159/000308465. Epub 2010 Jun 19.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [13] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [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] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [16] 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.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.