Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ZQSKS)

• DOT Name: Brain mitochondrial carrier protein 1 (SLC25A14)
• Synonyms: BMCP-1; Mitochondrial uncoupling protein 5; UCP 5; Solute carrier family 25 member 14
• Gene Name: SLC25A14
• UniProt ID: UCP5_HUMAN
• Pfam ID: PF00153
• Sequence:
  MGIFPGIILIFLRVKFATAAVIVSGHQKSTTVSHEMSGLNWKPFVYGGLASIVAEFGTFP
  VDLTKTRLQVQGQSIDARFKEIKYRGMFHALFRICKEEGVLALYSGIAPALLRQASYGTI
  KIGIYQSLKRLFVERLEDETLLINMICGVVSGVISSTIANPTDVLKIRMQAQGSLFQGSM
  IGSFIDIYQQEGTRGLWRGVVPTAQRAAIVVGVELPVYDITKKHLILSGMMGDTILTHFV
  SSFTCGLAGALASNPVDVVRTRMMNQRAIVGHVDLYKGTVDGILKMWKHEGFFALYKGFW
  PNWLRLGPWNIIFFITYEQLKRLQI
• Function: Transports inorganic anions (sulfate, sulfite, thiosulfate and phosphate) and, to a lesser extent, a variety of dicarboxylates (e.g. malonate, malate and citramalate) and, even more so, aspartate and glutamate and tricarboxylates. May catalyze the export of sulfite and thiosulfate (the hydrogen sulfide degradation products) from the mitochondria, thereby modulating the level of the hydrogen sulfide (Probable). Also can mediate a very low unidirectional transport of anions including sulfate, phosphate, (S)-malate, citrate, L-aspartate and L-glutamate. Maintains oxidative balance (through uncoupling activities) and ATP production (by modifying mitochondrial membrane potential). Is able to transport protons across lipid membranes. Also exhibits transmembrane chloride transport activity to a lesser extent. May modify mitochondrial respiratory efficiency and mitochondrial oxidant production.
• Tissue Specificity: Mainly expressed in brain . Some expression in testis and pituitary .
• Reactome Pathway:
  The proton buffering model (R-HSA-167827)
  The fatty acid cycling model (R-HSA-167826)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Brain mitochondrial carrier protein 1 (SLC25A14) decreases the chemical synthesis of Adenosine triphosphate.	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[5]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[6]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Brain mitochondrial carrier protein 1 (SLC25A14).	[9]

1 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 decreases the methylation of Brain mitochondrial carrier protein 1 (SLC25A14).	[8]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity. Free Radic Biol Med. 2010 Sep 15;49(6):1023-35. doi: 10.1016/j.freeradbiomed.2010.06.017. Epub 2010 Jun 19.
• [7] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.