Details of Drug Off-Target (DOT)

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

• DOT Name: NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10)
• Synonyms: Complex I-PDSW; CI-PDSW; NADH-ubiquinone oxidoreductase PDSW subunit
• Gene Name: NDUFB10
• Related Disease:
  Mitochondrial disease
  Mitochondrial complex I deficiency
  Mitochondrial complex 1 deficiency, nuclear type 35
• UniProt ID: NDUBA_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF10249
• Sequence:
  MPDSWDKDVYPEPPRRTPVQPNPIVYMMKAFDLIVDRPVTLVREFIERQHAKNRYYYYHR
  QYRRVPDITECKEEDIMCMYEAEMQWKRDYKVDQEIINIMQDRLKACQQREGQNYQQNCI
  KEVEQFTQVAKAYQDRYQDLGAYSSARKCLAKQRQRMLQERKAAKEAAAATS
• Function: Accessory subunit that is involved in the functional assembly of the mitochondrial respiratory chain complex I. Complex I has an NADH dehydrogenase activity with ubiquinone as an immediate electron acceptor and mediates the transfer of electrons from NADH to the respiratory chain.
• 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:HS06786-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[1]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[2]
Mitochondrial complex 1 deficiency, nuclear type 35	DISVL2EP	Limited	Unknown	[2]

4 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 beta subcomplex subunit 10 (NDUFB10).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[15]

11 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 beta subcomplex subunit 10 (NDUFB10).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 10 (NDUFB10).	[17]

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 accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly. Hum Mol Genet. 2017 Feb 15;26(4):702-716. doi: 10.1093/hmg/ddw431.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [10] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [11] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [12] 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.
• [13] 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.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.