Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYEB8YK)

• DOT Name: FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1)
• Synonyms: EC 1.-.-.-
• Gene Name: FOXRED1
• Related Disease:
  Mitochondrial complex I deficiency, nuclear type 1
  Mitochondrial disease
  Epilepsy
  High blood pressure
  Mitochondrial encephalomyopathy
  Leigh syndrome
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: FXRD1_HUMAN
• EC Number: 1.-.-.-
• Pfam ID: PF01266
• Sequence:
  MIRRVLPHGMGRGLLTRRPGTRRGGFSLDWDGKVSEIKKKIKSILPGRSCDLLQDTSHLP
  PEHSDVVIVGGGVLGLSVAYWLKKLESRRGAIRVLVVERDHTYSQASTGLSVGGICQQFS
  LPENIQLSLFSASFLRNINEYLAVVDAPPLDLRFNPSGYLLLASEKDAAAMESNVKVQRQ
  EGAKVSLMSPDQLRNKFPWINTEGVALASYGMEDEGWFDPWCLLQGLRRKVQSLGVLFCQ
  GEVTRFVSSSQRMLTTDDKAVVLKRIHEVHVKMDRSLEYQPVECAIVINAAGAWSAQIAA
  LAGVGEGPPGTLQGTKLPVEPRKRYVYVWHCPQGPGLETPLVADTSGAYFRREGLGSNYL
  GGRSPTEQEEPDPANLEVDHDFFQDKVWPHLALRVPAFETLKVQSAWAGYYDYNTFDQNG
  VVGPHPLVVNMYFATGFSGHGLQQAPGIGRAVAEMVLKGRFQTIDLSPFLFTRFYLGEKI
  QENNII
• Function: Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). Involved in mid-late stages of complex I assembly.

Molecular Interaction Atlas (MIA) of This DOT

8 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 disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[4]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Biomarker	[1]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[2]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[1]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[12]

8 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 FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1).	[15]

References

• [1] FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. Hum Mol Genet. 2010 Dec 15;19(24):4837-47. doi: 10.1093/hmg/ddq414. Epub 2010 Sep 21.
• [2] 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.
• [3] A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II.Mol Cell Biol. 2016 Jul 29;36(16):2132-40. doi: 10.1128/MCB.00066-16. Print 2016 Aug 15.
• [4] Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency.Mol Genet Metab Rep. 2019 Jan 18;18:32-38. doi: 10.1016/j.ymgmr.2018.12.006. eCollection 2019 Mar.
• [5] High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet. 2010 Oct;42(10):851-8. doi: 10.1038/ng.659. Epub 2010 Sep 5.
• [6] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.