Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ZNGEL)

• DOT Name: Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24)
• Synonyms: Mitochondrial ATP-Mg/Pi carrier protein 1; Mitochondrial Ca(2+)-dependent solute carrier protein 1; Short calcium-binding mitochondrial carrier protein 1; SCaMC-1; Solute carrier family 25 member 24
• Gene Name: SLC25A24
• Related Disease: Fontaine progeroid syndrome
• UniProt ID: SCMC1_HUMAN
• PDB ID: 4N5X; 4ZCU; 4ZCV
• Pfam ID: PF13499 ; PF00153
• Sequence:
  MLRWLRDFVLPTAACQDAEQPTRYETLFQALDRNGDGVVDIGELQEGLRNLGIPLGQDAE
  EKIFTTGDVNKDGKLDFEEFMKYLKDHEKKMKLAFKSLDKNNDGKIEASEIVQSLQTLGL
  TISEQQAELILQSIDVDGTMTVDWNEWRDYFLFNPVTDIEEIIRFWKHSTGIDIGDSLTI
  PDEFTEDEKKSGQWWRQLLAGGIAGAVSRTSTAPLDRLKIMMQVHGSKSDKMNIFGGFRQ
  MVKEGGIRSLWRGNGTNVIKIAPETAVKFWAYEQYKKLLTEEGQKIGTFERFISGSMAGA
  TAQTFIYPMEVMKTRLAVGKTGQYSGIYDCAKKILKHEGLGAFYKGYVPNLLGIIPYAGI
  DLAVYELLKSYWLDNFAKDSVNPGVMVLLGCGALSSTCGQLASYPLALVRTRMQAQAMLE
  GSPQLNMVGLFRRIISKEGIPGLYRGITPNFMKVLPAVGISYVVYENMKQTLGVTQK
• Function: Electroneutral antiporter that mediates the transport of adenyl nucleotides through the inner mitochondrial membrane. Originally identified as an ATP-magnesium/inorganic phosphate antiporter, it also acts as a broad specificity adenyl nucleotide antiporter. By regulating the mitochondrial matrix adenyl nucleotide pool could adapt to changing cellular energetic demands and indirectly regulate adenyl nucleotide-dependent metabolic pathways. In vitro, a low activity is also observed with guanyl and pyrimidine nucleotides. May play a role in protecting cells against oxidative stress-induced cell death, by buffering calcium levels in the mitochondrial matrix through the formation of calcium-phosphate precipitates.
• Tissue Specificity: Expressed in all tissues tested. Highly expressed in testis, expressed at intermediate level in small intestine and pancreas, and weakly expressed in kidney, spleen, liver, skeletal muscle and heart.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fontaine progeroid syndrome	DISJWGDF	Strong	Autosomal dominant	[1]

2 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 Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[12]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[13]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [13] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [14] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [15] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.