Details of Drug Off-Target (DOT)

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

• DOT Name: Iron-sulfur cluster transfer protein NUBPL (NUBPL)
• Synonyms: IND1 homolog; Nucleotide-binding protein-like; huInd1
• Gene Name: NUBPL
• Related Disease:
  Mitochondrial complex I deficiency, nuclear type 1
  Alzheimer disease
  Cardiac failure
  Colorectal carcinoma
  Dystonia
  Metastatic malignant neoplasm
  Mitochondrial complex 1 deficiency, nuclear type 21
  Mitochondrial disease
  Leigh syndrome
  Movement disorder
  Mitochondrial complex I deficiency
• UniProt ID: NUBPL_HUMAN
• Pfam ID: PF10609
• Sequence:
  MGIWQRLLLFGGVSLRAGGGATAPLGGSRAMVCGRQLSGAGSETLKQRRTQIMSRGLPKQ
  KPIEGVKQVIVVASGKGGVGKSTTAVNLALALAANDSSKAIGLLDVDVYGPSVPKMMNLK
  GNPELSQSNLMRPLLNYGIACMSMGFLVEESEPVVWRGLMVMSAIEKLLRQVDWGQLDYL
  VVDMPPGTGDVQLSVSQNIPITGAVIVSTPQDIALMDAHKGAEMFRRVHVPVLGLVQNMS
  VFQCPKCKHKTHIFGADGARKLAQTLGLEVLGDIPLHLNIREASDTGQPIVFSQPESDEA
  KAYLRIAVEVVRRLPSPSE
• Function: Iron-sulfur cluster transfer protein involved in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). May deliver one or more Fe-S clusters to complex I subunits.
• Tissue Specificity: Highest expression in liver and kidney. expressed at significant levels in small intestine and brain (at protein level).
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Cardiac failure	DISDC067	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Dystonia	DISJLFGW	Strong	Genetic Variation	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[4]
Mitochondrial complex 1 deficiency, nuclear type 21	DISG204L	Strong	Autosomal recessive	[6]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[7]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[8]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[9]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[6]

9 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 Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[19]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Iron-sulfur cluster transfer protein NUBPL (NUBPL).	[18]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] 3-(Benzyloxy)-1-(5-[(18)F]fluoropentyl)-5-nitro-1H-indazole: a PET radiotracer to measure acetylcholinesterase in brain.Future Med Chem. 2017 Jun;9(10):983-994. doi: 10.4155/fmc-2017-0023. Epub 2017 Jun 20.
• [3] Genetics of heart rate in heart failure patients (GenHRate).Hum Genomics. 2019 May 21;13(1):22. doi: 10.1186/s40246-019-0206-6.
• [4] NUBPL, a novel metastasis-related gene, promotes colorectal carcinoma cell motility by inducing epithelial-mesenchymal transition.Cancer Sci. 2017 Jun;108(6):1169-1176. doi: 10.1111/cas.13243. Epub 2017 Jun 14.
• [5] Mitochondrial complex I NUBPL mutations cause combined dystonia with bilateral striatal necrosis and cerebellar atrophy.Eur J Neurol. 2019 Sep;26(9):1240-1243. doi: 10.1111/ene.13956. Epub 2019 Apr 20.
• [6] High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet. 2010 Oct;42(10):851-8. doi: 10.1038/ng.659. Epub 2010 Sep 5.
• [7] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [8] 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.
• [9] NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern.Neurology. 2013 Apr 23;80(17):1577-83. doi: 10.1212/WNL.0b013e31828f1914. Epub 2013 Apr 3.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] 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.
• [17] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.