Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT64J803)

• DOT Name: Mitochondrial glutamate carrier 2 (SLC25A18)
• Synonyms: GC-2; Glutamate/H(+) symporter 2; Solute carrier family 25 member 18
• Gene Name: SLC25A18
• UniProt ID: GHC2_HUMAN
• Pfam ID: PF00153
• Sequence:
  MTHQDLSITAKLINGGVAGLVGVTCVFPIDLAKTRLQNQHGKAMYKGMIDCLMKTARAEG
  FFGMYRGAAVNLTLVTPEKAIKLAANDFFRRLLMEDGMQRNLKMEMLAGCGAGMCQVVVT
  CPMEMLKIQLQDAGRLAVHHQGSASAPSTSRSYTTGSASTHRRPSATLIAWELLRTQGLA
  GLYRGLGATLLRDIPFSIIYFPLFANLNNLGFNELAGKASFAHSFVSGCVAGSIAAVAVT
  PLDVLKTRIQTLKKGLGEDMYSGITDCARKLWIQEGPSAFMKGAGCRALVIAPLFGIAQG
  VYFIGIGERILKCFD
• Function: Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton (symport system).
• Tissue Specificity: Expressed in brain, to a lesser extent in testis, and poorly in all the other tissues.
• Reactome Pathway: Organic anion transporters (R-HSA-428643)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mitochondrial glutamate carrier 2 (SLC25A18).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial glutamate carrier 2 (SLC25A18).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial glutamate carrier 2 (SLC25A18).	[3]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Mitochondrial glutamate carrier 2 (SLC25A18).	[4]

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 increases the methylation of Mitochondrial glutamate carrier 2 (SLC25A18).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitochondrial glutamate carrier 2 (SLC25A18).	[6]

References

• [1] 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.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [5] 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.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.