Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4KF6Q5)

• DOT Name: Ferredoxin-2, mitochondrial (FDX2)
• Synonyms: Adrenodoxin-like protein; Ferredoxin-1-like protein
• Gene Name: FDX2
• Related Disease:
  Mitochondrial myopathy
  Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
  Myopathy
• UniProt ID: FDX2_HUMAN
• PDB ID: 2Y5C
• Pfam ID: PF00111
• Sequence:
  MAASMARGGVSARVLLQAARGTWWNRPGGTSGSGEGVALGTTRKFQATGSRPAGEEDAGG
  PERPGDVVNVVFVDRSGQRIPVSGRVGDNVLHLAQRHGVDLEGACEASLACSTCHVYVSE
  DHLDLLPPPEEREDDMLDMAPLLQENSRLGCQIVLTPELEGAEFTLPKITRNFYVDGHVP
  KPH
• Function: Electron donor, of the core iron-sulfur cluster (ISC) assembly complex, that acts to reduce the persulfide into sulfide during [2Fe-2S] clusters assembly on the scaffolding protein ISCU. 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.
• Tissue Specificity: Widely expressed, with highest levels in testis, kidney and brain (at protein level) . Expressed in muscle (at protein level) . Expressed in fibroblasts (at protein level) .
• Reactome Pathway:
  Pregnenolone biosynthesis (R-HSA-196108)
  Endogenous sterols (R-HSA-211976)
  Electron transport from NADPH to Ferredoxin (R-HSA-2395516)
  Defective CYP11A1 causes AICSR (R-HSA-5579026)
  Mitochondrial iron-sulfur cluster biogenesis (R-HSA-1362409)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[1]
Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy	DIS1YBKF	Strong	Autosomal recessive	[2]
Myopathy	DISOWG27	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ferredoxin-2, mitochondrial (FDX2).	[3]

5 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 Ferredoxin-2, mitochondrial (FDX2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ferredoxin-2, mitochondrial (FDX2).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ferredoxin-2, mitochondrial (FDX2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ferredoxin-2, mitochondrial (FDX2).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ferredoxin-2, mitochondrial (FDX2).	[8]

References

• [1] A novel complex neurological phenotype due to a homozygous mutation in FDX2.Brain. 2018 Aug 1;141(8):2289-2298. doi: 10.1093/brain/awy172.
• [2] Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy. Eur J Hum Genet. 2014 Jul;22(7):902-6. doi: 10.1038/ejhg.2013.269. Epub 2013 Nov 27.
• [3] 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.
• [4] 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.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.