Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL58QZS)

• DOT Name: NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1)
• Synonyms: HIRA-interacting protein 5
• Gene Name: NFU1
• Related Disease:
  Mitochondrial disease
  Multiple mitochondrial dysfunctions syndrome 1
  Lafora disease
  Leukodystrophy
  Myopathy
  High blood pressure
  Mitochondrial myopathy
• UniProt ID: NFU1_HUMAN
• PDB ID: 2LTM; 2M5O
• Pfam ID: PF08712 ; PF01106
• Sequence:
  MAATARRGWGAAAVAAGLRRRFCHMLKNPYTIKKQPLHQFVQRPLFPLPAAFYHPVRYMF
  IQTQDTPNPNSLKFIPGKPVLETRTMDFPTPAAAFRSPLARQLFRIEGVKSVFFGPDFIT
  VTKENEELDWNLLKPDIYATIMDFFASGLPLVTEETPSGEAGSEEDDEVVAMIKELLDTR
  IRPTVQEDGGDVIYKGFEDGIVQLKLQGSCTSCPSSIITLKNGIQNMLQFYIPEVEGVEQ
  VMDDESDEKEANSP
• Function: Iron-sulfur cluster scaffold protein which can assemble [4Fe-4S] clusters and deliver them to target proteins.
• Tissue Specificity: Ubiquitous. Expression in adult lung is weak compared to fetal lung.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Multiple mitochondrial dysfunctions syndrome 1	DISABZ3A	Definitive	Autosomal recessive	[2]
Lafora disease	DIS83JHH	Strong	Biomarker	[3]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[4]
Myopathy	DISOWG27	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[6]
Mitochondrial myopathy	DIS9SA7V	Limited	Genetic Variation	[7]

9 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 NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (NFU1).	[16]

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] A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am J Hum Genet. 2011 Nov 11;89(5):656-67. doi: 10.1016/j.ajhg.2011.10.005.
• [3] The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain.Hum Mol Genet. 2003 Sep 15;12(18):2359-68. doi: 10.1093/hmg/ddg253. Epub 2003 Jul 29.
• [4] Novel NFU1 Variants Induced MMDS Behaved as Special Leukodystrophy in Chinese Sufferers.J Mol Neurosci. 2017 Jun;62(2):255-261. doi: 10.1007/s12031-017-0927-8. Epub 2017 May 3.
• [5] Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.Am J Hum Genet. 2008 Mar;82(3):652-60. doi: 10.1016/j.ajhg.2007.12.012. Epub 2008 Feb 14.
• [6] Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension.Am J Respir Cell Mol Biol. 2020 Feb;62(2):231-242. doi: 10.1165/rcmb.2019-0065OC.
• [7] The presence of multiple cellular defects associated with a novel G50E iron-sulfur cluster scaffold protein (ISCU) mutation leads to development of mitochondrial myopathy.J Biol Chem. 2014 Apr 11;289(15):10359-10377. doi: 10.1074/jbc.M113.526665. Epub 2014 Feb 26.
• [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] 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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.