Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU230MC)

• DOT Name: Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1)
• Synonyms: HESB-like domain-containing protein 2; Iron-sulfur assembly protein IscA; hIscA
• Gene Name: ISCA1
• Related Disease:
  Fatal multiple mitochondrial dysfunctions syndrome
  Leukodystrophy
  Microcephaly
  Multiple mitochondrial dysfunctions syndrome 5
  Acute myelogenous leukaemia
• UniProt ID: ISCA1_HUMAN
• Pfam ID: PF01521
• Sequence:
  MSASLVRATVRAVSKRKLQPTRAALTLTPSAVNKIKQLLKDKPEHVGVKVGVRTRGCNGL
  SYTLEYTKTKGDSDEEVIQDGVRVFIEKKAQLTLLGTEMDYVEDKLSSEFVFNNPNIKGT
  CGCGESFNI
• Function: Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. Probably involved in the binding of an intermediate of Fe/S cluster assembly.
• Tissue Specificity: Detected in cerebellum, kidney and heart.
• 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
Fatal multiple mitochondrial dysfunctions syndrome	DISYBW5F	Strong	Genetic Variation	[1]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[2]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[1]
Multiple mitochondrial dysfunctions syndrome 5	DIS2OXH6	Strong	Autosomal recessive	[3]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[13]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Iron-sulfur cluster assembly 1 homolog, mitochondrial (ISCA1).	[16]

References

• [1] Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome.J Hum Genet. 2017 Jul;62(7):723-727. doi: 10.1038/jhg.2017.35. Epub 2017 Mar 30.
• [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] 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.
• [4] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [5] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.