Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLY5BAC)

• DOT Name: Tubby protein homolog
• Gene Name: TUB
• Related Disease:
  Retinal dystrophy and obesity
  Retinitis pigmentosa
  Essential tremor
• UniProt ID: TUB_HUMAN
• PDB ID: 1S31
• Pfam ID: PF01167 ; PF16322
• Sequence:
  MTSKPHSDWIPYSVLDDEGRNLRQQKLDRQRALLEQKQKKKRQEPLMVQANADGRPRSRR
  ARQSEEQAPLVESYLSSSGSTSYQVQEADSLASVQLGATRPTAPASAKRTKAAATAGGQG
  GAARKEKKGKHKGTSGPAALAEDKSEAQGPVQILTVGQSDHAQDAGETAAGGGERPSGQD
  LRATMQRKGISSSMSFDEDEEDEEENSSSSSQLNSNTRPSSATSRKSVREAASAPSPTAP
  EQPVDVEVQDLEEFALRPAPQGITIKCRITRDKKGMDRGMYPTYFLHLDREDGKKVFLLA
  GRKRKKSKTSNYLISVDPTDLSRGGDSYIGKLRSNLMGTKFTVYDNGVNPQKASSSTLES
  GTLRQELAAVCYETNVLGFKGPRKMSVIVPGMNMVHERVSIRPRNEHETLLARWQNKNTE
  SIIELQNKTPVWNDDTQSYVLNFHGRVTQASVKNFQIIHGNDPDYIVMQFGRVAEDVFTM
  DYNYPLCALQAFAIALSSFDSKLACE
• Function: Functions in signal transduction from heterotrimeric G protein-coupled receptors. Binds to membranes containing phosphatidylinositol 4,5-bisphosphate. Can bind DNA (in vitro). May contribute to the regulation of transcription in the nucleus. Could be involved in the hypothalamic regulation of body weight. Contribute to stimulation of phagocytosis of apoptotic retinal pigment epithelium (RPE) cells and macrophages.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinal dystrophy and obesity	DISSJRZ7	Strong	Autosomal recessive	[1]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[2]
Essential tremor	DIS7GBKQ	Limited	Autosomal dominant	[3]

2 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 Tubby protein homolog.	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tubby protein homolog.	[12]

11 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 Tubby protein homolog.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tubby protein homolog.	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tubby protein homolog.	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Tubby protein homolog.	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tubby protein homolog.	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tubby protein homolog.	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tubby protein homolog.	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Tubby protein homolog.	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tubby protein homolog.	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tubby protein homolog.	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tubby protein homolog.	[15]

References

• [1] Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation. Mol Cell Biol. 2000 Feb;20(3):878-82. doi: 10.1128/MCB.20.3.878-882.2000.
• [2] A homozygous mutation in the TUB gene associated with retinal dystrophy and obesity. Hum Mutat. 2014 Mar;35(3):289-93. doi: 10.1002/humu.22482. Epub 2013 Dec 20.
• [3] 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.
• [4] 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.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget. 2014 Dec 30;5(24):12891-907.
• [12] 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.
• [13] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.