Details of Drug Off-Target (DOT)

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

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2)
• Synonyms: Complex I-B8; CI-B8; NADH-ubiquinone oxidoreductase B8 subunit
• Gene Name: NDUFA2
• Related Disease:
  Acute myelogenous leukaemia
  Arteriosclerosis
  Atherosclerosis
  Coeliac disease
  Cushing disease
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Mitochondrial complex 1 deficiency, nuclear type 13
  Mitochondrial disease
  Parkinson disease
  Vitamin A deficiency
  Leigh syndrome
  Cystic leukoencephalopathy without megalencephaly
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: NDUA2_HUMAN
• PDB ID: 1S3A; 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF05047
• Sequence:
  MAAAAASRGVGAKLGLREIRIHLCQRSPGSQGVRDFIEKRYVELKKANPDLPILIRECSD
  VQPKLWARYAFGQETNVPLNNFSADQVTRALENVLSGKA
• 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:HS05539-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[2]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[3]
Cushing disease	DISOG6P2	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[5]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[5]
Mitochondrial complex 1 deficiency, nuclear type 13	DISYJ1EV	Strong	Autosomal recessive	[6]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[7]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[8]
Vitamin A deficiency	DISBEPZO	Strong	Biomarker	[9]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[10]
Cystic leukoencephalopathy without megalencephaly	DISSYSPD	Supportive	Autosomal recessive	[11]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PEITC	DMOMN31	Phase 2	NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2) affects the binding of PEITC.	[26]

13 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 2 (NDUFA2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[25]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of NADH dehydrogenase 1 alpha subcomplex subunit 2 (NDUFA2).	[19]

References

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• [11] Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy. Clin Genet. 2018 Feb;93(2):396-400. doi: 10.1111/cge.13126. Epub 2017 Dec 21.
• [12] 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.
• [13] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
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• [17] 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.
• [18] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [19] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [20] 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.
• [21] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [25] Exosomes mediated the delivery of ochratoxin A-induced cytotoxicity in HEK293 cells. Toxicology. 2021 Sep;461:152926. doi: 10.1016/j.tox.2021.152926. Epub 2021 Sep 3.
• [26] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.