Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR848KZ)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5)
• Synonyms: Complex I subunit B13; Complex I-13kD-B; CI-13kD-B; NADH-ubiquinone oxidoreductase 13 kDa-B subunit
• Gene Name: NDUFA5
• Related Disease:
  Alzheimer disease
  Autism
  Cardiomyopathy
  Chagas disease
  Lactic acidosis
  Leigh syndrome
  Acute myelogenous leukaemia
• UniProt ID: NDUA5_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF04716
• Sequence:
  MAGVLKKTTGLVGLAVCNTPHERLRILYTKILDVLEEIPKNAAYRKYTEQITNEKLAMVK
  AEPDVKKLEDQLQGGQLEEVILQAEHELNLARKMREWKLWEPLVEEPPADQWKWPI
• 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.
• Tissue Specificity: Expressed in all tissues examined with highest levels in heart, skeletal muscle and brain.
• 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:HS05206-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[3]
Chagas disease	DIS8KNVF	Strong	Biomarker	[3]
Lactic acidosis	DISZI1ZK	Strong	Biomarker	[4]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[12]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[14]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[16]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 5 (NDUFA5).	[17]

References

• [1] A serial analysis of gene expression profile of the Alzheimer's disease Tg2576 mouse model.Neurotox Res. 2010 May;17(4):360-79. doi: 10.1007/s12640-009-9112-3. Epub 2009 Sep 16.
• [2] The NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism.Acta Psychiatr Scand. 2011 Feb;123(2):118-24. doi: 10.1111/j.1600-0447.2010.01600.x. Epub 2010 Sep 5.
• [3] T cell epitope characterization in tandemly repetitive Trypanosoma cruzi B13 protein.Microbes Infect. 2005 Aug-Sep;7(11-12):1184-95. doi: 10.1016/j.micinf.2005.03.033.
• [4] Nuclear DNA origin of mitochondrial complex I deficiency in fatal infantile lactic acidosis evidenced by transnuclear complementation of cultured fibroblasts.J Clin Invest. 1999 Jul;104(1):83-92. doi: 10.1172/JCI6184.
• [5] Mitochondrial DNA mutations in Leigh syndrome and their phylogenetic implications.J Hum Genet. 2000;45(2):69-75. doi: 10.1007/s100380050014.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [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] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [17] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.