Details of Drug Off-Target (DOT)

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

• DOT Name: Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2)
• Synonyms: HESB-like domain-containing protein 1
• Gene Name: ISCA2
• Related Disease:
  Mitochondrial disease
  Multiple mitochondrial dysfunctions syndrome 3
  Fatal multiple mitochondrial dysfunctions syndrome
  Multiple mitochondrial dysfunctions syndrome 4
  Leukodystrophy
• UniProt ID: ISCA2_HUMAN
• Pfam ID: PF01521
• Sequence:
  MAAAWGSSLTAATQRAVTPWPRGRLLTASLGPQARREASSSSPEAGEGQIRLTDSCVQRL
  LEITEGSEFLRLQVEGGGCSGFQYKFSLDTVINPDDRVFEQGGARVVVDSDSLAFVKGAQ
  VDFSQELIRSSFQVLNNPQAQQGCSCGSSFSIKL
• Function: Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. May be involved in the binding of an intermediate of Fe/S cluster assembly.
• Reactome Pathway: Mitochondrial iron-sulfur cluster biogenesis (R-HSA-1362409)

Molecular Interaction Atlas (MIA) of This DOT

5 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 3	DISTIUPO	Definitive	Genetic Variation	[2]
Fatal multiple mitochondrial dysfunctions syndrome	DISYBW5F	Strong	Genetic Variation	[3]
Multiple mitochondrial dysfunctions syndrome 4	DIS42DWP	Strong	Autosomal recessive	[4]
Leukodystrophy	DISVY1TT	Limited	Biomarker	[5]

1 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 Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[6]

7 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 Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2).	[13]

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] ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.Hum Mol Genet. 2018 Aug 1;27(15):2739-2754. doi: 10.1093/hmg/ddy183.
• [3] Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015 Jan 13;10(2):148-61. doi: 10.1016/j.celrep.2014.12.015. Epub 2014 Dec 31.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Further delineation of the phenotypic spectrum ofISCA2 defect: A report of ten new cases.Eur J Paediatr Neurol. 2018 Jan;22(1):46-55. doi: 10.1016/j.ejpn.2017.10.003. Epub 2017 Oct 16.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.