Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTZVSK6)

• DOT Name: Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13)
• Synonyms: Calcium-binding mitochondrial carrier protein Aralar2; ARALAR-related gene 2; ARALAR2; Citrin; Mitochondrial aspartate glutamate carrier 2; Solute carrier family 25 member 13
• Gene Name: SLC25A13
• Related Disease:
  Citrin deficiency
  Citrullinemia, type II, adult-onset
  Citrullinemia type II
  Neonatal intrahepatic cholestasis due to citrin deficiency
• UniProt ID: S2513_HUMAN
• PDB ID: 4P5W
• Pfam ID: PF00153
• Sequence:
  MAAAKVALTKRADPAELRTIFLKYASIEKNGEFFMSPNDFVTRYLNIFGESQPNPKTVEL
  LSGVVDQTKDGLISFQEFVAFESVLCAPDALFMVAFQLFDKAGKGEVTFEDVKQVFGQTT
  IHQHIPFNWDSEFVQLHFGKERKRHLTYAEFTQFLLEIQLEHAKQAFVQRDNARTGRVTA
  IDFRDIMVTIRPHVLTPFVEECLVAAAGGTTSHQVSFSYFNGFNSLLNNMELIRKIYSTL
  AGTRKDVEVTKEEFVLAAQKFGQVTPMEVDILFQLADLYEPRGRMTLADIERIAPLEEGT
  LPFNLAEAQRQKASGDSARPVLLQVAESAYRFGLGSVAGAVGATAVYPIDLVKTRMQNQR
  STGSFVGELMYKNSFDCFKKVLRYEGFFGLYRGLLPQLLGVAPEKAIKLTVNDFVRDKFM
  HKDGSVPLAAEILAGGCAGGSQVIFTNPLEIVKIRLQVAGEITTGPRVSALSVVRDLGFF
  GIYKGAKACFLRDIPFSAIYFPCYAHVKASFANEDGQVSPGSLLLAGAIAGMPAASLVTP
  ADVIKTRLQVAARAGQTTYSGVIDCFRKILREEGPKALWKGAGARVFRSSPQFGVTLLTY
  ELLQRWFYIDFGGVKPMGSEPVPKSRINLPAPNPDHVGGYKLAVATFAGIENKFGLYLPL
  FKPSVSTSKAIGGGP
• 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: High levels in liver and low levels in kidney, pancreas, placenta, heart and brain.
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Citrin deficiency	DISIJZ2R	Definitive	Autosomal recessive	[1]
Citrullinemia, type II, adult-onset	DISJFLV7	Strong	Autosomal recessive	[2]
Citrullinemia type II	DIS2UURN	Supportive	Autosomal recessive	[3]
Neonatal intrahepatic cholestasis due to citrin deficiency	DIS8XETO	Supportive	Autosomal recessive	[3]

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 Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[9]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[10]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial (SLC25A13).	[15]

References

• [1] 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.
• [2] The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet. 1999 Jun;22(2):159-63. doi: 10.1038/9667.
• [3] Citrin Deficiency. 2005 Sep 16 [updated 2017 Aug 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] 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.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] 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.
• [10] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [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.