Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB4YBVT)

• DOT Name: Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12)
• Synonyms: Araceli hiperlarga; Aralar; Aralar1; Mitochondrial aspartate glutamate carrier 1; Solute carrier family 25 member 12
• Gene Name: SLC25A12
• Related Disease:
  Developmental and epileptic encephalopathy, 39
  Mitochondrial disease
• UniProt ID: S2512_HUMAN
• PDB ID: 4P5X; 4P60
• Pfam ID: PF00153
• Sequence:
  MAVKVQTTKRGDPHELRNIFLQYASTEVDGERYMTPEDFVQRYLGLYNDPNSNPKIVQLL
  AGVADQTKDGLISYQEFLAFESVLCAPDSMFIVAFQLFDKSGNGEVTFENVKEIFGQTII
  HHHIPFNWDCEFIRLHFGHNRKKHLNYTEFTQFLQELQLEHARQAFALKDKSKSGMISGL
  DFSDIMVTIRSHMLTPFVEENLVSAAGGSISHQVSFSYFNAFNSLLNNMELVRKIYSTLA
  GTRKDVEVTKEEFAQSAIRYGQVTPLEIDILYQLADLYNASGRLTLADIERIAPLAEGAL
  PYNLAELQRQQSPGLGRPIWLQIAESAYRFTLGSVAGAVGATAVYPIDLVKTRMQNQRGS
  GSVVGELMYKNSFDCFKKVLRYEGFFGLYRGLIPQLIGVAPEKAIKLTVNDFVRDKFTRR
  DGSVPLPAEVLAGGCAGGSQVIFTNPLEIVKIRLQVAGEITTGPRVSALNVLRDLGIFGL
  YKGAKACFLRDIPFSAIYFPVYAHCKLLLADENGHVGGLNLLAAGAMAGVPAASLVTPAD
  VIKTRLQVAARAGQTTYSGVIDCFRKILREEGPSAFWKGTAARVFRSSPQFGVTLVTYEL
  LQRWFYIDFGGLKPAGSEPTPKSRIADLPPANPDHIGGYRLATATFAGIENKFGLYLPKF
  KSPSVAVVQPKAAVAATQ
• Function: Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle. Also mediates the uptake of L-cysteinesulfinate by mitochondria in exchange of L-glutamate and proton. Can also exchange L-cysteinesulfinate with aspartate in their anionic form without any proton translocation.
• Tissue Specificity: Expressed predominantly in the heart and skeletal muscle, weakly in brain and kidney.
• Reactome Pathway:
  Gluconeogenesis (R-HSA-70263)
  Aspartate and asparagine metabolism (R-HSA-8963693)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 39	DISA15DM	Strong	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[2]

20 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 Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (SLC25A12).	[20]

References

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• [2] 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.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] 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.
• [13] 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.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.