Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIRMB2O)

• DOT Name: NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7)
• Synonyms: EC 7.1.1.2; Complex I-20kD; CI-20kD; NADH-ubiquinone oxidoreductase 20 kDa subunit; PSST subunit
• Gene Name: NDUFS7
• Related Disease:
  Mitochondrial complex I deficiency, nuclear type 1
  Mitochondrial complex 1 deficiency, nuclear type 3
  Leigh syndrome
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: NDUS7_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF01058
• Sequence:
  MAVLSAPGLRGFRILGLRSSVGPAVQARGVHQSVATDGPSSTQPALPKARAVAPKPSSRG
  EYVVAKLDDLVNWARRSSLWPMTFGLACCAVEMMHMAAPRYDMDRFGVVFRASPRQSDVM
  IVAGTLTNKMAPALRKVYDQMPEPRYVVSMGSCANGGGYYHYSYSVVRGCDRIVPVDIYI
  PGCPPTAEALLYGILQLQRKIKRERRLQIWYRR
• 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.
• 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:HS03864-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Definitive	Autosomal recessive	[1]
Mitochondrial complex 1 deficiency, nuclear type 3	DIS3XJ22	Strong	Autosomal recessive	[2]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[3]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[4]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[5]

7 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 iron-sulfur protein 7, mitochondrial (NDUFS7).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7).	[10]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7).	[13]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH dehydrogenase iron-sulfur protein 7, mitochondrial (NDUFS7).	[12]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I. Ann Neurol. 1999 Jun;45(6):787-90. doi: 10.1002/1531-8249(199906)45:6<787::aid-ana13>3.0.co;2-6.
• [3] 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.
• [4] Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis. 2012 Sep;35(5):737-47. doi: 10.1007/s10545-012-9492-z. Epub 2012 May 30.
• [5] A novel mutation in the human complex I NDUFS7 subunit associated with Leigh syndrome. Mol Genet Metab. 2007 Apr;90(4):379-82. doi: 10.1016/j.ymgme.2006.12.007. Epub 2007 Feb 1.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [10] 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.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] 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.
• [13] 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.