Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0XMVWH)

• DOT Name: Mitochondrial brown fat uncoupling protein 1
• Synonyms: UCP 1; Solute carrier family 25 member 7; Thermogenin
• Gene Name: UCP1
• UniProt ID: UCP1_HUMAN
• PDB ID: 8G8W; 8HBV; 8HBW; 8J1N
• Pfam ID: PF00153
• Sequence:
  MGGLTASDVHPTLGVQLFSAGIAACLADVITFPLDTAKVRLQVQGECPTSSVIRYKGVLG
  TITAVVKTEGRMKLYSGLPAGLQRQISSASLRIGLYDTVQEFLTAGKETAPSLGSKILAG
  LTTGGVAVFIGQPTEVVKVRLQAQSHLHGIKPRYTGTYNAYRIIATTEGLTGLWKGTTPN
  LMRSVIINCTELVTYDLMKEAFVKNNILADDVPCHLVSALIAGFCATAMSSPVDVVKTRF
  INSPPGQYKSVPNCAMKVFTNEGPTAFFKGLVPSFLRLGSWNVIMFVCFEQLKRELSKSR
  QTMDCAT
• Function: Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance. Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane. However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria.
• Tissue Specificity: Brown adipose tissue.
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Apelin sig.ling pathway (hsa04371)
  Thermogenesis (hsa04714)
  Huntington disease (hsa05016)
• Reactome Pathway:
  The proton buffering model (R-HSA-167827)
  The fatty acid cycling model (R-HSA-167826)

Molecular Interaction Atlas (MIA) of This DOT

14 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 brown fat uncoupling protein 1.	[1]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Mitochondrial brown fat uncoupling protein 1.	[2]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mitochondrial brown fat uncoupling protein 1.	[3]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Mitochondrial brown fat uncoupling protein 1.	[4]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Mitochondrial brown fat uncoupling protein 1.	[2]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Mitochondrial brown fat uncoupling protein 1.	[5]
Tofacitinib	DMBS370	Approved	Tofacitinib increases the expression of Mitochondrial brown fat uncoupling protein 1.	[6]
Nevirapine	DM6HX9B	Approved	Nevirapine increases the expression of Mitochondrial brown fat uncoupling protein 1.	[7]
Abacavir	DMMN36E	Approved	Abacavir increases the expression of Mitochondrial brown fat uncoupling protein 1.	[5]
Stavudine	DM6DEK9	Approved	Stavudine increases the expression of Mitochondrial brown fat uncoupling protein 1.	[7]
Jakafi	DMNORK8	Phase 3	Jakafi increases the expression of Mitochondrial brown fat uncoupling protein 1.	[6]
PF-02545920	DMJPE61	Phase 2	PF-02545920 increases the expression of Mitochondrial brown fat uncoupling protein 1.	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitochondrial brown fat uncoupling protein 1.	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mitochondrial brown fat uncoupling protein 1.	[2]

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 decreases the methylation of Mitochondrial brown fat uncoupling protein 1.	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitochondrial brown fat uncoupling protein 1.	[10]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [2] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [3] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [4] Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):292-8.
• [5] Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther. 2003 Aug;8(4):323-31.
• [6] White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
• [7] Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes. Antivir Ther. 2005;10(4):515-26.
• [8] A novel thermoregulatory role for PDE10A in mouse and human adipocytes. EMBO Mol Med. 2016 Jul 1;8(7):796-812. doi: 10.15252/emmm.201506085. Print 2016 Jul.
• [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.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.