Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIT3Y14)

• DOT Name: TBC1 domain family member 15 (TBC1D15)
• Synonyms: GTPase-activating protein RAB7; GAP for RAB7; Rab7-GAP
• Gene Name: TBC1D15
• UniProt ID: TBC15_HUMAN
• Pfam ID: PF12068 ; PF00566
• Sequence:
  MAAAGVVSGKIIYEQEGVYIHSSCGKTNDQDGLISGILRVLEKDAEVIVDWRPLDDALDS
  SSILYARKDSSSVVEWTQAPKERGHRGSEHLNSYEAEWDMVNTVSFKRKPHTNGDAPSHR
  NGKSKWSFLFSLTDLKSIKQNKEGMGWSYLVFCLKDDVVLPALHFHQGDSKLLIESLEKY
  VVLCESPQDKRTLLVNCQNKSLSQSFENLLDEPAYGLIQAGLLDRRKLLWAIHHWKKIKK
  DPYTATMIGFSKVTNYIFDSLRGSDPSTHQRPPSEMADFLSDAIPGLKINQQEEPGFEVI
  TRIDLGERPVVQRREPVSLEEWTKNIDSEGRILNVDNMKQMIFRGGLSHALRKQAWKFLL
  GYFPWDSTKEERTQLQKQKTDEYFRMKLQWKSISQEQEKRNSRLRDYRSLIEKDVNRTDR
  TNKFYEGQDNPGLILLHDILMTYCMYDFDLGYVQGMSDLLSPLLYVMENEVDAFWCFASY
  MDQMHQNFEEQMQGMKTQLIQLSTLLRLLDSGFCSYLESQDSGYLYFCFRWLLIRFKREF
  SFLDILRLWEVMWTELPCTNFHLLLCCAILESEKQQIMEKHYGFNEILKHINELSMKIDV
  EDILCKAEAISLQMVKCKELPQAVCEILGLQGSEVTTPDSDVGEDENVVMTPCPTSAFQS
  NALPTLSASGARNDSPTQIPVSSDVCRLTPA
• Function: Acts as a GTPase activating protein for RAB7A. Does not act on RAB4, RAB5 or RAB6.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway: TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of TBC1 domain family member 15 (TBC1D15).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of TBC1 domain family member 15 (TBC1D15).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of TBC1 domain family member 15 (TBC1D15).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TBC1 domain family member 15 (TBC1D15).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of TBC1 domain family member 15 (TBC1D15).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of TBC1 domain family member 15 (TBC1D15).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of TBC1 domain family member 15 (TBC1D15).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TBC1 domain family member 15 (TBC1D15).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of TBC1 domain family member 15 (TBC1D15).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of TBC1 domain family member 15 (TBC1D15).	[8]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of TBC1 domain family member 15 (TBC1D15).	[9]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of TBC1 domain family member 15 (TBC1D15).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of TBC1 domain family member 15 (TBC1D15).	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of TBC1 domain family member 15 (TBC1D15).	[14]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of TBC1 domain family member 15 (TBC1D15).	[15]

References

• [1] 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.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [10] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [11] 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.
• [12] 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.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [14] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [15] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.