Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE9U09A)

• DOT Name: Frataxin, mitochondrial (FXN)
• Synonyms: EC 1.16.3.1; Friedreich ataxia protein; Fxn
• Gene Name: FXN
• Related Disease:
  Friedreich's ataxia
  Friedreich ataxia 1
  Obsolete Friedreich ataxia
• UniProt ID: FRDA_HUMAN
• PDB ID: 1EKG; 1LY7; 3S4M; 3S5D; 3S5E; 3S5F; 3T3J; 3T3K; 3T3L; 3T3T; 3T3X; 5KZ5; 6NZU
• EC Number: 1.16.3.1
• Pfam ID: PF01491
• Sequence:
  MWTLGRRAVAGLLASPSPAQAQTLTRVPRPAELAPLCGRRGLRTDIDATCTPRRASSNQR
  GLNQIWNVKKQSVYLMNLRKSGTLGHPGSLDETTYERLAEETLDSLAEFFEDLADKPYTF
  EDYDVSFGSGVLTVKLGGDLGTYVINKQTPNKQIWLSSPSSGPKRYDWTGKNWVYSHDGV
  SLHELLAAELTKALKTKLDLSSLAYSGKDA
• Function: [Frataxin mature form]: Functions as an activator of persulfide transfer to the scaffoding protein ISCU as component of the core iron-sulfur cluster (ISC) assembly complex and participates to the [2Fe-2S] cluster assembly. Accelerates sulfur transfer from NFS1 persulfide intermediate to ISCU and to small thiols such as L-cysteine and glutathione leading to persulfuration of these thiols and ultimately sulfide release. Binds ferrous ion and is released from FXN upon the addition of both L-cysteine and reduced FDX2 during [2Fe-2S] cluster assembly. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. May function as an iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes enzyme reactivation. May play a role as a high affinity iron binding partner for FECH that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis ; [Extramitochondrial frataxin]: Modulates the RNA-binding activity of ACO1. May be involved in the cytoplasmic iron-sulfur protein biogenesis. May contribute to oxidative stress resistance and overall cell survival.
• Tissue Specificity: Expressed in the heart, peripheral blood lymphocytes and dermal fibroblasts.
• KEGG Pathway: Porphyrin metabolism (hsa00860)
• Reactome Pathway:
  Mitochondrial iron-sulfur cluster biogenesis (R-HSA-1362409)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Friedreich's ataxia	DIS5DV35	Definitive	Autosomal recessive	[1]
Friedreich ataxia 1	DIS285GE	Strong	Autosomal recessive	[2]
Obsolete Friedreich ataxia	DISDEWJV	Supportive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Frataxin, mitochondrial (FXN) decreases the response to substance of Hydrogen peroxide.	[17]

16 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 Frataxin, mitochondrial (FXN).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Frataxin, mitochondrial (FXN).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Frataxin, mitochondrial (FXN).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Frataxin, mitochondrial (FXN).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Frataxin, mitochondrial (FXN).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Frataxin, mitochondrial (FXN).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Frataxin, mitochondrial (FXN).	[10]
Ethanol	DMDRQZU	Approved	Ethanol affects the expression of Frataxin, mitochondrial (FXN).	[11]
Betamethasone	DMAHJEF	Approved	Betamethasone increases the expression of Frataxin, mitochondrial (FXN).	[12]
Deferiprone	DMS2M7O	Approved	Deferiprone increases the expression of Frataxin, mitochondrial (FXN).	[12]
Molsidomine	DM9MA8O	Approved	Molsidomine increases the expression of Frataxin, mitochondrial (FXN).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Frataxin, mitochondrial (FXN).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Frataxin, mitochondrial (FXN).	[12]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Frataxin, mitochondrial (FXN).	[12]
RG-2833	DM7B650	Phase 1	RG-2833 increases the expression of Frataxin, mitochondrial (FXN).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Frataxin, mitochondrial (FXN).	[16]

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 Frataxin, mitochondrial (FXN).	[14]

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] Clinical and genetic study of Friedreich ataxia in an Australian population. Am J Med Genet. 1999 Nov 19;87(2):168-74. doi: 10.1002/(sici)1096-8628(19991119)87:2<168::aid-ajmg8>3.0.co;2-2.
• [3] Structure-function analysis of Friedreich's ataxia mutants reveals determinants of frataxin binding and activation of the Fe-S assembly complex. Biochemistry. 2011 Aug 23;50(33):7265-74. doi: 10.1021/bi200895k. Epub 2011 Aug 2.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] 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.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis. Toxicology. 2020 Dec 1;445:152584. doi: 10.1016/j.tox.2020.152584. Epub 2020 Oct 2.
• [12] Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia. PLoS One. 2013;8(2):e55940.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Epigenetic therapy for Friedreich ataxia. Ann Neurol. 2014 Oct;76(4):489-508. doi: 10.1002/ana.24260. Epub 2014 Sep 16.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Mesenchymal stem cells restore frataxin expression and increase hydrogen peroxide scavenging enzymes in Friedreich ataxia fibroblasts. PLoS One. 2011;6(10):e26098. doi: 10.1371/journal.pone.0026098. Epub 2011 Oct 7.