Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXL10N9)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3)
• Synonyms: Complex I-B9; CI-B9; NADH-ubiquinone oxidoreductase B9 subunit
• Gene Name: NDUFA3
• UniProt ID: NDUA3_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF14987
• Sequence:
  MAARVGAFLKNAWDKEPVLVVSFVVGGLAVILPPLSPYFKYSVMINKATPYNYPVPVRDD
  GNMPDVPSHPQDPQGPSLEWLKKL
• 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:HS10204-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3) affects the response to substance of Paclitaxel.	[18]
Vinblastine	DM5TVS3	Approved	NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3) 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 1 alpha subcomplex subunit 3 (NDUFA3).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[13]

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 1 alpha subcomplex subunit 3 (NDUFA3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[16]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3).	[17]

References

• [1] 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.
• [2] 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.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] 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.
• [10] 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.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [15] 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.
• [16] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [17] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [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.