Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSW6DQP)

• DOT Name: Iron-sulfur cluster assembly enzyme ISCU (ISCU)
• Synonyms: NifU-like N-terminal domain-containing protein; NifU-like protein
• Gene Name: ISCU
• Related Disease:
  Advanced cancer
  Hepatocellular carcinoma
  Mitochondrial disease
  B-cell neoplasm
  Breast cancer
  Coeliac disease
  Friedreich ataxia 1
  Friedreich's ataxia
  Hereditary myopathy with lactic acidosis due to ISCU deficiency
  Mitochondrial myopathy
  Myopathy
  Neoplasm
  Paraganglioma
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Sideroblastic anemia
  Adult lymphoma
  Childhood acute megakaryoblastic leukemia
  Lactic acidosis
  Lymphoma
  Pediatric lymphoma
• UniProt ID: ISCU_HUMAN
• PDB ID: 5KZ5; 5WKP; 5WLW; 6NZU; 6UXE; 6W1D; 6WI2; 6WIH; 7RTK
• Pfam ID: PF01592
• Sequence:
  MAAAGAFRLRRAASALLLRSPRLPARELSAPARLYHKKVVDHYENPRNVGSLDKTSKNVG
  TGLVGAPACGDVMKLQIQVDEKGKIVDARFKTFGCGSAIASSSLATEWVKGKTVEEALTI
  KNTDIAKELCLPPVKLHCSMLAEDAIKAALADYKLKQEPKKGEAEKK
• Function: [Isoform 1]: Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled. 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 (Probable). Exists as two slow interchanging conformational states, a structured (S) and disordered (D) form. May modulate NFS1 desulfurase activity in a zinc-dependent manner. Modulates the interaction between FXN and the cysteine desulfurase complex ; [Isoform 2]: Cytoplasmic scaffold protein, of the cytoplasmic core iron-sulfur cluster (ISC) assembly complex that provides the structural architecture on which the Fe-S clusters are assembled and may be involved in the cytoplasmic iron-sulfur protein biogenesis.
• Tissue Specificity: Detected in heart, liver, skeletal muscle, brain, pancreas, kidney, lung and placenta.
• Reactome Pathway: Maturation of replicase proteins (R-HSA-9694301)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Genetic Variation	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
B-cell neoplasm	DISVY326	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Coeliac disease	DISIY60C	Strong	Altered Expression	[5]
Friedreich ataxia 1	DIS285GE	Strong	Genetic Variation	[6]
Friedreich's ataxia	DIS5DV35	Strong	Genetic Variation	[7]
Hereditary myopathy with lactic acidosis due to ISCU deficiency	DISJHOGS	Strong	Autosomal recessive	[8]
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[9]
Myopathy	DISOWG27	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[11]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Biomarker	[3]
Sideroblastic anemia	DIS4F3X1	Strong	Biomarker	[12]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[13]
Childhood acute megakaryoblastic leukemia	DIS5VZDR	Limited	Biomarker	[14]
Lactic acidosis	DISZI1ZK	Limited	Genetic Variation	[15]
Lymphoma	DISN6V4S	Limited	Biomarker	[13]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[13]

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 enzyme ISCU (ISCU).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[24]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Iron-sulfur cluster assembly enzyme ISCU (ISCU).	[29]

References

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• [8] Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. Hum Mol Genet. 2008 Jun 1;17(11):1666-72. doi: 10.1093/hmg/ddn057. Epub 2008 Feb 23.
• [9] The presence of multiple cellular defects associated with a novel G50E iron-sulfur cluster scaffold protein (ISCU) mutation leads to development of mitochondrial myopathy.J Biol Chem. 2014 Apr 11;289(15):10359-10377. doi: 10.1074/jbc.M113.526665. Epub 2014 Feb 26.
• [10] Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines.Hum Mol Genet. 2016 Dec 1;25(23):5178-5187. doi: 10.1093/hmg/ddw338.
• [11] SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas.J Clin Endocrinol Metab. 2018 Jan 1;103(1):295-305. doi: 10.1210/jc.2017-01702.
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• [15] The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be derepressed by IGF2BP1.Hum Mutat. 2012 Mar;33(3):467-70. doi: 10.1002/humu.22002. Epub 2011 Dec 29.
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• [18] 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.
• [19] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [20] Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology. 2015 Feb 3;328:102-11. doi: 10.1016/j.tox.2014.12.018. Epub 2014 Dec 18.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [23] 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.
• [24] 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.
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• [29] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.