Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB78IF4)

• DOT Name: Mitochondrial 2-oxodicarboxylate carrier (SLC25A21)
• Synonyms: ODC; Mitochondrial 2-oxoadipate carrier; Solute carrier family 25 member 21
• Gene Name: SLC25A21
• Related Disease: Mitochondrial DNA depletion syndrome 18
• UniProt ID: ODC_HUMAN
• Pfam ID: PF00153
• Sequence:
  MSAKPEVSLVREASRQIVAGGSAGLVEICLMHPLDVVKTRFQIQRCATDPNSYKSLVDSF
  RMIFQMEGLFGFYKGILPPILAETPKRAVKFFTFEQYKKLLGYVSLSPALTFAIAGLGSG
  LTEAIVVNPFEVVKVGLQANRNTFAEQPSTVGYARQIIKKEGWGLQGLNKGLTATLGRHG
  VFNMVYFGFYYNVKNMIPVNKDPILEFWRKFGIGLLSGTIASVINIPFDVAKSRIQGPQP
  VPGEIKYRTCFKTMATVYQEEGILALYKGLLPKIMRLGPGGAVMLLVYEYTYSWLQENW
• Function: Transports dicarboxylates across the inner membranes of mitochondria by a counter-exchange mechanism. Can transport 2-oxoadipate (2-oxohexanedioate), 2-oxoglutarate, adipate (hexanedioate), glutarate, and to a lesser extent, pimelate (heptanedioate), 2-oxopimelate (2-oxoheptanedioate), 2-aminoadipate (2-aminohexanedioate), oxaloacetate, and citrate. Plays a central role in catabolism of lysine, hydroxylysine, and tryptophan, by transporting common metabolite intermediates (such as 2-oxoadipate) into the mitochondria, where it is converted into acetyl-CoA and can enter the citric acid (TCA) cycle (Probable).
• Tissue Specificity: Expressed in placenta, gall bladder and colon.
• Reactome Pathway: Lysine catabolism (R-HSA-71064)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial DNA depletion syndrome 18	DISMJS4T	Limited	Autosomal recessive	[1]

12 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 2-oxodicarboxylate carrier (SLC25A21).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[4]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[5]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Mitochondrial 2-oxodicarboxylate carrier (SLC25A21).	[12]

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] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [3] 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.
• [4] 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.
• [5] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [6] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] 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.
• [11] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [12] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.