Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQGVI1N)

• DOT Name: Mitochondrial glutamate carrier 1 (SLC25A22)
• Synonyms: GC-1; Glutamate/H(+) symporter 1; Solute carrier family 25 member 22
• Gene Name: SLC25A22
• Related Disease:
  Infantile spasm
  Developmental and epileptic encephalopathy, 3
  Early myoclonic encephalopathy
  Malignant migrating partial seizures of infancy
• UniProt ID: GHC1_HUMAN
• Pfam ID: PF00153
• Sequence:
  MADKQISLPAKLINGGIAGLIGVTCVFPIDLAKTRLQNQQNGQRVYTSMSDCLIKTVRSE
  GYFGMYRGAAVNLTLVTPEKAIKLAANDFFRHQLSKDGQKLTLLKEMLAGCGAGTCQVIV
  TTPMEMLKIQLQDAGRIAAQRKILAAQGQLSAQGGAQPSVEAPAAPRPTATQLTRDLLRS
  RGIAGLYKGLGATLLRDVPFSVVYFPLFANLNQLGRPASEEKSPFYVSFLAGCVAGSAAA
  VAVNPCDVVKTRLQSLQRGVNEDTYSGILDCARKILRHEGPSAFLKGAYCRALVIAPLFG
  IAQVVYFLGIAESLLGLLQDPQA
• Function: Mitochondrial glutamate/H(+) symporter. Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton. Plays a role in the control of glucose-stimulated insulin secretion.
• Tissue Specificity: Expressed at high levels in brain, liver, and pancreas.
• Reactome Pathway: Organic anion transporters (R-HSA-428643)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal recessive	[1]
Developmental and epileptic encephalopathy, 3	DISJY2DN	Strong	Autosomal recessive	[2]
Early myoclonic encephalopathy	DIS1YXVQ	Supportive	Autosomal dominant	[3]
Malignant migrating partial seizures of infancy	DISF2TRU	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Mitochondrial glutamate carrier 1 (SLC25A22).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mitochondrial glutamate carrier 1 (SLC25A22).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[12]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Mitochondrial glutamate carrier 1 (SLC25A22).	[17]

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] 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.
• [3] Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum Genet. 2005 Feb;76(2):334-9.
• [4] SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol. 2013 Dec;74(6):873-82. doi: 10.1002/ana.23998.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] 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.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] 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.
• [13] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [14] 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.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] 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.