Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBT8KW9)

• DOT Name: NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2)
• Synonyms: EC 7.1.1.2; Complex I-49kD; CI-49kD; NADH-ubiquinone oxidoreductase 49 kDa subunit
• Gene Name: NDUFS2
• Related Disease:
  Leigh syndrome
  Mitochondrial complex I deficiency, nuclear type 1
  Mitochondrial complex 1 deficiency, nuclear type 6
  Leber hereditary optic neuropathy
  Leigh syndrome with cardiomyopathy
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: NDUS2_HUMAN
• PDB ID: 5XTB; 5XTC; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF00346
• Sequence:
  MAALRALCGFRGVAAQVLRPGAGVRLPIQPSRGVRQWQPDVEWAQQFGGAVMYPSKETAH
  WKPPPWNDVDPPKDTIVKNITLNFGPQHPAAHGVLRLVMELSGEMVRKCDPHIGLLHRGT
  EKLIEYKTYLQALPYFDRLDYVSMMCNEQAYSLAVEKLLNIRPPPRAQWIRVLFGEITRL
  LNHIMAVTTHALDLGAMTPFFWLFEEREKMFEFYERVSGARMHAAYIRPGGVHQDLPLGL
  MDDIYQFSKNFSLRLDELEELLTNNRIWRNRTIDIGVVTAEEALNYGFSGVMLRGSGIQW
  DLRKTQPYDVYDQVEFDVPVGSRGDCYDRYLCRVEEMRQSLRIIAQCLNKMPPGEIKVDD
  AKVSPPKRAEMKTSMESLIHHFKLYTEGYQVPPGATYTAIEAPKGEFGVYLVSDGSSRPY
  RCKIKAPGFAHLAGLDKMSKGHMLADVVAIIGTQDIVFGEVDR
• Function: Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity of complex I. Essential for the assembly of complex I. Redox-sensitive, critical component of the oxygen-sensing pathway in the pulmonary vasculature which plays a key role in acute pulmonary oxygen-sensing and hypoxic pulmonary vasoconstriction. Plays an important role in carotid body sensing of hypoxia. Essential for glia-like neural stem and progenitor cell proliferation, differentiation and subsequent oligodendrocyte or neuronal maturation.
• 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:HS08339-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
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[1]
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Definitive	Autosomal recessive	[2]
Mitochondrial complex 1 deficiency, nuclear type 6	DISML9YM	Strong	Autosomal recessive	[3]
Leber hereditary optic neuropathy	DIS7Y2EE	Supportive	Mitochondrial	[4]
Leigh syndrome with cardiomyopathy	DIS2UELC	Supportive	Autosomal recessive	[5]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[6]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[7]

3 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 2, mitochondrial (NDUFS2).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[21]

14 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 iron-sulfur protein 2, mitochondrial (NDUFS2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[17]
Cocaine	DMSOX7I	Approved	Cocaine affects the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[18]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2).	[24]

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] Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy. Ann Neurol. 2001 Feb;49(2):195-201. doi: 10.1002/1531-8249(20010201)49:2<195::aid-ana39>3.0.co;2-m.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy. J Med Genet. 2017 May;54(5):346-356. doi: 10.1136/jmedgenet-2016-104212. Epub 2016 Dec 28.
• [5] A catalytic defect in mitochondrial respiratory chain complex I due to a mutation in NDUFS2 in a patient with Leigh syndrome. Biochim Biophys Acta. 2012 Feb;1822(2):168-75. doi: 10.1016/j.bbadis.2011.10.012. Epub 2011 Oct 20.
• [6] Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta. 2004 Dec 6;1659(2-3):136-47. doi: 10.1016/j.bbabio.2004.09.006.
• [7] Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene. 2013 Mar 1;516(1):162-7. doi: 10.1016/j.gene.2012.12.024. Epub 2012 Dec 22.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [15] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [18] Proteomic analysis of the nucleus accumbens of rats with different vulnerability to cocaine addiction. Neuropharmacology. 2009 Jul;57(1):41-8. doi: 10.1016/j.neuropharm.2009.04.005. Epub 2009 Apr 22.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [23] 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.
• [24] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.