Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTMZA4Q)

• DOT Name: NADH-ubiquinone oxidoreductase chain 4L (ND4L)
• Synonyms: EC 7.1.1.2; NADH dehydrogenase subunit 4L; ND4L
• Gene Name: ND4L
• Related Disease: Neoplasm
• UniProt ID: NU4LM_HUMAN
• PDB ID: 5XTC; 5XTD
• EC Number: 7.1.1.2
• Pfam ID: PF00420
• Sequence:
  MPLIYMNIMLAFTISLLGMLVYRSHLMSSLLCLEGMMLSLFIMATLMTLNTHSLLANIVP
  IAMLVFAACEAAVGLALLVSISNTYGLDYVHNLNLLQC
• 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. Part of the enzyme membrane arm which is embedded in the lipid bilayer and involved in proton translocation.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  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)
• BioCyc Pathway: MetaCyc:HS00034-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Disputed	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of NADH-ubiquinone oxidoreductase chain 4L (ND4L).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADH-ubiquinone oxidoreductase chain 4L (ND4L).	[3]
Marinol	DM70IK5	Approved	Marinol increases the expression of NADH-ubiquinone oxidoreductase chain 4L (ND4L).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of NADH-ubiquinone oxidoreductase chain 4L (ND4L).	[5]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH-ubiquinone oxidoreductase chain 4L (ND4L).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH-ubiquinone oxidoreductase chain 4L (ND4L).	[7]

References

• [1] Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck.Proc Natl Acad Sci U S A. 2007 May 1;104(18):7540-5. doi: 10.1073/pnas.0610818104. Epub 2007 Apr 24.
• [2] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] 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.
• [4] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [7] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.