Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT30QA56)

• DOT Name: Target of Myb1 membrane trafficking protein (TOM1)
• Synonyms: Target of Myb protein 1
• Gene Name: TOM1
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Bipolar disorder
  Cystic fibrosis
  Mood disorder
  Plasma cell myeloma
  Acute lymphocytic leukaemia
  Immune system disorder
  Immunodeficiency 85 and autoimmunity
  Ulcerative colitis
• UniProt ID: TOM1_HUMAN
• PDB ID: 1ELK; 1WRD; 2N2N; 2N9D; 6J56
• Pfam ID: PF03127 ; PF00790
• Sequence:
  MDFLLGNPFSSPVGQRIEKATDGSLQSEDWALNMEICDIINETEEGPKDALRAVKKRIVG
  NKNFHEVMLALTVLETCVKNCGHRFHVLVASQDFVESVLVRTILPKNNPPTIVHDKVLNL
  IQSWADAFRSSPDLTGVVTIYEDLRRKGLEFPMTDLDMLSPIHTPQRTVFNSETQSGQDS
  VGTDSSQQEDSGQHAAPLPAPPILSGDTPIAPTPEQIGKLRSELEMVSGNVRVMSEMLTE
  LVPTQAEPADLELLQELNRTCRAMQQRVLELIPQIANEQLTEELLIVNDNLNNVFLRHER
  FERFRTGQTTKAPSEAEPAADLIDMGPDPAATGNLSSQLAGMNLGSSSVRAGLQSLEASG
  RLEDEFDMFALTRGSSLADQRKEVKYEAPQATDGLAGALDARQQSTGAIPVTQACLMEDI
  EQWLSTDVGNDAEEPKGVTSEEFDKFLEERAKAADRLPNLSSPSAEGPPGPPSGPAPRKK
  TQEKDDDMLFAL
• Function: Adapter protein that plays a role in the intracellular membrane trafficking of ubiquitinated proteins, thereby participating in autophagy, ubiquitination-dependent signaling and receptor recycling pathways. Acts as a MYO6/Myosin VI adapter protein that targets MYO6 to endocytic structures. Together with MYO6, required for autophagosomal delivery of endocytic cargo, the maturation of autophagosomes and their fusion with lysosomes. MYO6 links TOM1 with autophagy receptors, such as TAX1BP1; CALCOCO2/NDP52 and OPTN. Binds to polyubiquitinated proteins via its GAT domain. In a complex with TOLLIP, recruits ubiquitin-conjugated proteins onto early endosomes. The Tom1-Tollip complex may regulate endosomal trafficking by linking polyubiquitinated proteins to clathrin. Mediates clathrin recruitment to early endosomes by ZFYVE16. Modulates binding of TOLLIP to phosphatidylinositol 3-phosphate (PtdIns(3)P) via binding competition; the association with TOLLIP may favor the release of TOLLIP from endosomal membranes, allowing TOLLIP to commit to cargo trafficking. Acts as a phosphatidylinositol 5-phosphate (PtdIns(5)P) effector by binding to PtdIns(5)P, thereby regulating endosomal maturation. PtdIns(5)P-dependent recruitment to signaling endosomes may block endosomal maturation. Also inhibits Toll-like receptor (TLR) signaling and participates in immune receptor recycling.
• Tissue Specificity: Widely expressed. Highly expressed in skeletal muscle, heart, placenta and liver.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[3]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[4]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[5]
Acute lymphocytic leukaemia	DISPX75S	Disputed	Biomarker	[6]
Immune system disorder	DISAEGPH	Limited	Autosomal dominant	[7]
Immunodeficiency 85 and autoimmunity	DISFOD7V	Limited	Unknown	[8]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[9]

8 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 Target of Myb1 membrane trafficking protein (TOM1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Target of Myb1 membrane trafficking protein (TOM1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Target of Myb1 membrane trafficking protein (TOM1).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Target of Myb1 membrane trafficking protein (TOM1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Target of Myb1 membrane trafficking protein (TOM1).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Target of Myb1 membrane trafficking protein (TOM1).	[15]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Target of Myb1 membrane trafficking protein (TOM1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Target of Myb1 membrane trafficking protein (TOM1).	[18]

3 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 affects the methylation of Target of Myb1 membrane trafficking protein (TOM1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Target of Myb1 membrane trafficking protein (TOM1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Target of Myb1 membrane trafficking protein (TOM1).	[17]

References

• [1] Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.Proc Natl Acad Sci U S A. 2019 Oct 15;116(42):21198-21206. doi: 10.1073/pnas.1914088116. Epub 2019 Sep 30.
• [2] TOM1 Regulates Neuronal Accumulation of Amyloid- Oligomers by FcRIIb2 Variant in Alzheimer's Disease.J Neurosci. 2018 Oct 17;38(42):9001-9018. doi: 10.1523/JNEUROSCI.1996-17.2018. Epub 2018 Sep 5.
• [3] Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: association with HMG2L1 and TOM1.Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 5;147B(1):59-67. doi: 10.1002/ajmg.b.30574.
• [4] miR-126 is downregulated in cystic fibrosis airway epithelial cells and regulates TOM1 expression.J Immunol. 2010 Feb 15;184(4):1702-9. doi: 10.4049/jimmunol.0902669. Epub 2010 Jan 18.
• [5] Genome-wide association study identifies multiple susceptibility loci for multiple myeloma.Nat Commun. 2016 Jul 1;7:12050. doi: 10.1038/ncomms12050.
• [6] Effect of Aplidin in acute lymphoblastic leukaemia cells.Br J Cancer. 2003 Aug 18;89(4):763-73. doi: 10.1038/sj.bjc.6601130.
• [7] 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.
• [8] Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease. NPJ Genom Med. 2019 Jun 27;4:14. doi: 10.1038/s41525-019-0088-5. eCollection 2019.
• [9] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] 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.
• [13] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [14] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [15] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [16] 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.
• [17] 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.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.