Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI9V7B0)

• DOT Name: TBC1 domain family member 1 (TBC1D1)
• Gene Name: TBC1D1
• Related Disease:
  Neoplasm
  Congenital anomaly of kidney and urinary tract
  Hyperglycemia
  Non-insulin dependent diabetes
  Osteoarthritis
  Renal dysplasia
  Schizophrenia
  Tuberculosis
  Cardiomyopathy
  Type-1/2 diabetes
• UniProt ID: TBCD1_HUMAN
• PDB ID: 3QYE
• Pfam ID: PF11830 ; PF00640 ; PF00566
• Sequence:
  MEPITFTARKHLLSNEVSVDFGLQLVGSLPVHSLTTMPMLPWVVAEVRRLSRQSTRKEPV
  TKQVRLCVSPSGLRCEPEPGRSQQWDPLIYSSIFECKPQRVHKLIHNSHDPSYFACLIKE
  DAVHRQSICYVFKADDQTKVPEIISSIRQAGKIARQEELHCPSEFDDTFSKKFEVLFCGR
  VTVAHKKAPPALIDECIEKFNHVSGSRGSESPRPNPPHAAPTGSQEPVRRPMRKSFSQPG
  LRSLAFRKELQDGGLRSSGFFSSFEESDIENHLISGHNIVQPTDIEENRTMLFTIGQSEV
  YLISPDTKKIALEKNFKEISFCSQGIRHVDHFGFICRESSGGGGFHFVCYVFQCTNEALV
  DEIMMTLKQAFTVAAVQQTAKAPAQLCEGCPLQSLHKLCERIEGMNSSKTKLELQKHLTT
  LTNQEQATIFEEVQKLRPRNEQRENELIISFLRCLYEEKQKEHIHIGEMKQTSQMAAENI
  GSELPPSATRFRLDMLKNKAKRSLTESLESILSRGNKARGLQEHSISVDLDSSLSSTLSN
  TSKEPSVCEKEALPISESSFKLLGSSEDLSSDSESHLPEEPAPLSPQQAFRRRANTLSHF
  PIECQEPPQPARGSPGVSQRKLMRYHSVSTETPHERKDFESKANHLGDSGGTPVKTRRHS
  WRQQIFLRVATPQKACDSSSRYEDYSELGELPPRSPLEPVCEDGPFGPPPEEKKRTSREL
  RELWQKAILQQILLLRMEKENQKLQASENDLLNKRLKLDYEEITPCLKEVTTVWEKMLST
  PGRSKIKFDMEKMHSAVGQGVPRHHRGEIWKFLAEQFHLKHQFPSKQQPKDVPYKELLKQ
  LTSQQHAILIDLGRTFPTHPYFSAQLGAGQLSLYNILKAYSLLDQEVGYCQGLSFVAGIL
  LLHMSEEEAFKMLKFLMFDMGLRKQYRPDMIILQIQMYQLSRLLHDYHRDLYNHLEEHEI
  GPSLYAAPWFLTMFASQFPLGFVARVFDMIFLQGTEVIFKVALSLLGSHKPLILQHENLE
  TIVDFIKSTLPNLGLVQMEKTINQVFEMDIAKQLQAYEVEYHVLQEELIDSSPLSDNQRM
  DKLEKTNSSLRKQNLDLLEQLQVANGRIQSLEATIEKLLSSESKLKQAMLTLELERSALL
  QTVEELRRRSAEPSDREPECTQPEPTGD
• Function: May act as a GTPase-activating protein for Rab family protein(s). May play a role in the cell cycle and differentiation of various tissues. Involved in the trafficking and translocation of GLUT4-containing vesicles and insulin-stimulated glucose uptake into cells.
• KEGG Pathway: AMPK sig.ling pathway (hsa04152)
• Reactome Pathway: Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Strong	Biomarker	[2]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[4]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[5]
Renal dysplasia	DIS3DFGD	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[6]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[7]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	Limited	Posttranslational Modification	[9]

4 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 TBC1 domain family member 1 (TBC1D1).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of TBC1 domain family member 1 (TBC1D1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TBC1 domain family member 1 (TBC1D1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of TBC1 domain family member 1 (TBC1D1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of TBC1 domain family member 1 (TBC1D1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of TBC1 domain family member 1 (TBC1D1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of TBC1 domain family member 1 (TBC1D1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of TBC1 domain family member 1 (TBC1D1).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of TBC1 domain family member 1 (TBC1D1).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of TBC1 domain family member 1 (TBC1D1).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of TBC1 domain family member 1 (TBC1D1).	[17]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of TBC1 domain family member 1 (TBC1D1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of TBC1 domain family member 1 (TBC1D1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TBC1 domain family member 1 (TBC1D1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of TBC1 domain family member 1 (TBC1D1).	[22]

References

• [1] TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB.Oncogene. 2010 Jun 24;29(25):3619-29. doi: 10.1038/onc.2010.116. Epub 2010 Apr 26.
• [2] Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT).Hum Genet. 2016 Jan;135(1):69-87. doi: 10.1007/s00439-015-1610-1. Epub 2015 Nov 16.
• [3] Endurance running exercise is an effective alternative to estradiol replacement for restoring hyperglycemia through TBC1D1/GLUT4 pathway in skeletal muscle of ovariectomized rats.J Physiol Sci. 2019 Nov;69(6):1029-1040. doi: 10.1007/s12576-019-00723-3. Epub 2019 Nov 28.
• [4] RabGAPs in skeletal muscle function and exercise.J Mol Endocrinol. 2020 Jan;64(1):R1-R19. doi: 10.1530/JME-19-0143.
• [5] Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.Lancet. 2012 Sep 1;380(9844):815-23. doi: 10.1016/S0140-6736(12)60681-3. Epub 2012 Jul 3.
• [6] Exploratory study on association of genetic variation in TBC1D1 with antipsychotic-induced weight gain.Hum Psychopharmacol. 2013 Mar;28(2):183-7. doi: 10.1002/hup.2288. Epub 2013 Jan 30.
• [7] Evaluation of the hyplex TBC PCR test for detection of Mycobacterium tuberculosis complex in clinical samples.BMC Microbiol. 2010 Mar 31;10:95. doi: 10.1186/1471-2180-10-95.
• [8] Ablating the Rab-GTPase activating protein TBC1D1 predisposes rats to high-fat diet-induced cardiomyopathy.J Physiol. 2020 Feb;598(4):683-697. doi: 10.1113/JP279042. Epub 2020 Feb 4.
• [9] Personalized epigenetic management of diabetes.Per Med. 2017 Nov;14(6):531-549. doi: 10.2217/pme-2017-0043. Epub 2017 Nov 24.
• [10] 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.
• [11] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [12] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [15] 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.
• [16] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [19] 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.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.