Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSF2NXD)

• DOT Name: Mitochondrial S-adenosylmethionine carrier protein (SLC25A26)
• Synonyms: SAM carrier; Solute carrier family 25 member 26
• Gene Name: SLC25A26
• Related Disease:
  Mitochondrial disease
  Combined oxidative phosphorylation deficiency 28
• UniProt ID: SAMC_HUMAN
• Pfam ID: PF00153
• Sequence:
  MDRPGFVAALVAGGVAGVSVDLILFPLDTIKTRLQSPQGFSKAGGFHGIYAGVPSAAIGS
  FPNAAAFFITYEYVKWFLHADSSSYLTPMKHMLAASAGEVVACLIRVPSEVVKQRAQVSA
  STRTFQIFSNILYEEGIQGLYRGYKSTVLREIPFSLVQFPLWESLKALWSWRQDHVVDSW
  QSAVCGAFAGGFAAAVTTPLDVAKTRITLAKAGSSTADGNVLSVLHGVWRSQGLAGLFAG
  VFPRMAAISLGGFIFLGAYDRTHSLLLEVGRKSP
• Function: Mitochondrial S-adenosyl-L-methionine/S-adenosyl-L-homocysteine antiporter. Mediates the exchange of cytosolic S-adenosyl-L-methionine, the predominant methyl-group donor for macromolecule methylation processes, for mitochondrial S-adenosylhomocysteine(SAH), a by-product of methylation reactions.
• Tissue Specificity: Widely expressed. Highly expressed in testis, with moderate expression in brain, heart, kidney, lung, skeletal muscle, pancreas, small intestine and liver, and low expression in spleen.
• Reactome Pathway: Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Combined oxidative phosphorylation deficiency 28	DISRUR5T	Strong	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[8]

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 affects the methylation of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitochondrial S-adenosylmethionine carrier protein (SLC25A26).	[10]

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 Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [8] 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.
• [9] 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.
• [10] 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.