Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7EVFBK)

• DOT Name: Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11)
• Synonyms: OGCP; alpha-oxoglutarate carrier; Solute carrier family 25 member 11; SLC25A11
• Gene Name: SLC25A11
• Related Disease:
  Hereditary pheochromocytoma-paraganglioma
  Paragangliomas 6
• UniProt ID: M2OM_HUMAN
• Pfam ID: PF00153
• Sequence:
  MAATASAGAGGIDGKPRTSPKSVKFLFGGLAGMGATVFVQPLDLVKNRMQLSGEGAKTRE
  YKTSFHALTSILKAEGLRGIYTGLSAGLLRQATYTTTRLGIYTVLFERLTGADGTPPGFL
  LKAVIGMTAGATGAFVGTPAEVALIRMTADGRLPADQRRGYKNVFNALIRITREEGVLTL
  WRGCIPTMARAVVVNAAQLASYSQSKQFLLDSGYFSDNILCHFCASMISGLVTTAASMPV
  DIAKTRIQNMRMIDGKPEYKNGLDVLFKVVRYEGFFSLWKGFTPYYARLGPHTVLTFIFL
  EQMNKAYKRLFLSG
• Function: Catalyzes the transport of 2-oxoglutarate (alpha-oxoglutarate) across the inner mitochondrial membrane in an electroneutral exchange for malate. Can also exchange 2-oxoglutarate for other dicarboxylic acids such as malonate, succinate, maleate and oxaloacetate, although with lower affinity. Contributes to several metabolic processes, including the malate-aspartate shuttle, the oxoglutarate/isocitrate shuttle, in gluconeogenesis from lactate, and in nitrogen metabolism. Maintains mitochondrial fusion and fission events, and the organization and morphology of cristae. Involved in the regulation of apoptosis. Helps protect from cytotoxic-induced apoptosis by modulating glutathione levels in mitochondria.
• Tissue Specificity: Most highly expressed in the heart.
• Reactome Pathway: Gluconeogenesis (R-HSA-70263)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Supportive	Autosomal dominant	[1]
Paragangliomas 6	DISZ3QST	Limited	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11) increases the Mitochondrial toxicity ADR of Ethanol.	[17]

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 Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11).	[13]

References

• [1] Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer Res. 2018 Apr 15;78(8):1914-1922. doi: 10.1158/0008-5472.CAN-17-2463. Epub 2018 Feb 5.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] 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.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.