Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDEDY0S)

• DOT Name: BolA-like protein 3 (BOLA3)
• Gene Name: BOLA3
• Related Disease:
  Multiple mitochondrial dysfunctions syndrome 1
  Fatal multiple mitochondrial dysfunctions syndrome
  Glycine encephalopathy
  Multiple mitochondrial dysfunctions syndrome 2
  Cardiomyopathy
  High blood pressure
  Hypertrophic cardiomyopathy
  Leukodystrophy
• UniProt ID: BOLA3_HUMAN
• PDB ID: 2NCL
• Pfam ID: PF01722
• Sequence:
  MAAWSPAAAAPLLRGIRGLPLHHRMFATQTEGELRVTQILKEKFPRATAIKVTDISGGCG
  AMYEIKIESEEFKEKRTVQQHQMVNQALKEEIKEMHGLRIFTSVPKR
• Function: Acts as a mitochondrial iron-sulfur (Fe-S) cluster assembly factor that facilitates (Fe-S) cluster insertion into a subset of mitochondrial proteins. Probably acts together with NFU1.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple mitochondrial dysfunctions syndrome 1	DISABZ3A	Definitive	Biomarker	[1]
Fatal multiple mitochondrial dysfunctions syndrome	DISYBW5F	Strong	Biomarker	[2]
Glycine encephalopathy	DISI2XE5	Strong	Genetic Variation	[3]
Multiple mitochondrial dysfunctions syndrome 2	DISOBNE1	Strong	Autosomal recessive	[4]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[5]
High blood pressure	DISY2OHH	Limited	Biomarker	[6]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[7]
Leukodystrophy	DISVY1TT	Limited	Biomarker	[5]

12 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 BolA-like protein 3 (BOLA3).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of BolA-like protein 3 (BOLA3).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of BolA-like protein 3 (BOLA3).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BolA-like protein 3 (BOLA3).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BolA-like protein 3 (BOLA3).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of BolA-like protein 3 (BOLA3).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of BolA-like protein 3 (BOLA3).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of BolA-like protein 3 (BOLA3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of BolA-like protein 3 (BOLA3).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of BolA-like protein 3 (BOLA3).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BolA-like protein 3 (BOLA3).	[20]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of BolA-like protein 3 (BOLA3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of BolA-like protein 3 (BOLA3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of BolA-like protein 3 (BOLA3).	[19]

References

• [1] 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.
• [2] 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.
• [3] Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain. 2014 Feb;137(Pt 2):366-79. doi: 10.1093/brain/awt328. Epub 2013 Dec 11.
• [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] Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy.Am J Med Genet A. 2018 Dec;176(12):2787-2790. doi: 10.1002/ajmg.a.40490. Epub 2018 Oct 10.
• [6] BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.Circulation. 2019 May 7;139(19):2238-2255. doi: 10.1161/CIRCULATIONAHA.118.035889.
• [7] An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation.Brain Dev. 2018 Jun;40(6):484-488. doi: 10.1016/j.braindev.2018.02.004. Epub 2018 Mar 2.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.