Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5NGRWC)

• DOT Name: Solute carrier family 25 member 47 (SLC25A47)
• Synonyms: Hepatocellular carcinoma down-regulated mitochondrial carrier protein; Mitochondrial NAD(+) transporter SLC25A47
• Gene Name: SLC25A47
• Related Disease:
  Fatty liver disease
  Hepatocellular carcinoma
  Non-alcoholic steatohepatitis
• UniProt ID: S2547_HUMAN
• Pfam ID: PF00153
• Sequence:
  MDFVAGAIGGVCGVAVGYPLDTVKVRIQTEPKYTGIWHCVRDTYHRERVWGFYRGLSLPV
  CTVSLVSSVSFGTYRHCLAHICRLRYGNPDAKPTKADITLSGCASGLVRVFLTSPTEVAK
  VRLQTQTQAQKQQRRLSASGPLAVPPMCPVPPACPEPKYRGPLHCLATVAREEGLCGLYK
  GSSALVLRDGHSFATYFLSYAVLCEWLSPAGHSRPDVPGVLVAGGCAGVLAWAVATPMDV
  IKSRLQADGQGQRRYRGLLHCMVTSVREEGPRVLFKGLVLNCCRAFPVNMVVFVAYEAVL
  RLARGLLT
• Function: Mitochondrial NAD(+) transporter that acts as a 'metabolic gate' in hepatic lipogenesis. Provides NAD(+) substrate to mitochondrial SIRT3 deacetylase and enables its NAD(+)-dependent activities in mitochondrial energy metabolism. This triggers downstream activation of PRKAA1/AMPK-alpha signaling cascade that negatively regulates sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance. May transport other mitochondrial metabolites having an aromatic nucleotide and phosphate groups, such as acetyl-CoA. Does not transport amino acids. The transport mechanism remains to be elucidated.
• Tissue Specificity: Specifically expressed in liver.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Non-alcoholic steatohepatitis	DIST4788	Strong	Altered Expression	[1]

3 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 Solute carrier family 25 member 47 (SLC25A47).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Solute carrier family 25 member 47 (SLC25A47).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Solute carrier family 25 member 47 (SLC25A47).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 25 member 47 (SLC25A47).	[4]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Solute carrier family 25 member 47 (SLC25A47).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Solute carrier family 25 member 47 (SLC25A47).	[7]

References

• [1] Effect of miR-146 targeted HDMCP up-regulation in the pathogenesis of nonalcoholic steatohepatitis.PLoS One. 2017 Mar 27;12(3):e0174218. doi: 10.1371/journal.pone.0174218. eCollection 2017.
• [2] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.