Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN5V274)

• DOT Name: Arginine-hydroxylase NDUFAF5, mitochondrial (NDUFAF5)
• Synonyms: EC 1.-.-.-; NADH dehydrogenase 1 alpha subcomplex assembly factor 5; Putative methyltransferase NDUFAF5; EC 2.1.1.-
• Gene Name: NDUFAF5
• Related Disease:
  Leigh syndrome
  Mitochondrial complex 1 deficiency, nuclear type 16
  Mitochondrial disease
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: NDUF5_HUMAN
• EC Number: 1.-.-.-; 2.1.1.-
• Pfam ID: PF08241
• Sequence:
  MLRPAGLWRLCRRPWAARVPAENLGRREVTSGVSPRGSTSPRTLNIFDRDLKRKQKNWAA
  RQPEPTKFDYLKEEVGSRIADRVYDIPRNFPLALDLGCGRGYIAQYLNKETIGKFFQADI
  AENALKNSSETEIPTVSVLADEEFLPFKENTFDLVVSSLSLHWVNDLPRALEQIHYILKP
  DGVFIGAMFGGDTLYELRCSLQLAETEREGGFSPHISPFTAVNDLGHLLGRAGFNTLTVD
  TDEIQVNYPGMFELMEDLQGMGESNCAWNRKALLHRDTMLAAAAVYREMYRNEDGSVPAT
  YQIYYMIGWKYHESQARPAERGSATVSFGELGKINNLMPPGKKSQ
• Function: Arginine hydroxylase involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages. Acts by mediating hydroxylation of 'Arg-111' of NDUFS7. May also have methyltransferase activity (Probable).
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

5 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 1 deficiency, nuclear type 16	DISV3C9P	Strong	Autosomal recessive	[2]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[3]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[4]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Arginine-hydroxylase NDUFAF5, mitochondrial (NDUFAF5).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Arginine-hydroxylase NDUFAF5, mitochondrial (NDUFAF5).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Arginine-hydroxylase NDUFAF5, mitochondrial (NDUFAF5).	[7]

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] 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.
• [3] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [4] Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. Am J Hum Genet. 2008 Oct;83(4):468-78. doi: 10.1016/j.ajhg.2008.09.009.
• [5] Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome. J Med Genet. 2010 Aug;47(8):507-12. doi: 10.1136/jmg.2009.067553. Epub 2009 Jun 18.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.