Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSS1CK4)

• DOT Name: Tubulin--tyrosine ligase (TTL)
• Synonyms: TTL; EC 6.3.2.25
• Gene Name: TTL
• Related Disease:
  Malignant soft tissue neoplasm
  Neoplasm
  Sarcoma
  Advanced cancer
  Fibrosarcoma
  Hepatocellular carcinoma
  Neuroblastoma
• UniProt ID: TTL_HUMAN
• PDB ID: 8ASN
• EC Number: 6.3.2.25
• Pfam ID: PF03133
• Sequence:
  MYTFVVRDENSSVYAEVSRLLLATGHWKRLRRDNPRFNLMLGERNRLPFGRLGHEPGLVQ
  LVNYYRGADKLCRKASLVKLIKTSPELAESCTWFPESYVIYPTNLKTPVAPAQNGIQPPI
  SNSRTDEREFFLASYNRKKEDGEGNVWIAKSSAGAKGEGILISSEASELLDFIDNQGQVH
  VIQKYLEHPLLLEPGHRKFDIRSWVLVDHQYNIYLYREGVLRTASEPYHVDNFQDKTCHL
  TNHCIQKEYSKNYGKYEEGNEMFFKEFNQYLTSALNITLESSILLQIKHIIRNCLLSVEP
  AISTKHLPYQSFQLFGFDFMVDEELKVWLIEVNGAPACAQKLYAELCQGIVDIAISSVFP
  PPDVEQPQTQPAAFIKL
• Function: Catalyzes the post-translational addition of a tyrosine to the C-terminal end of detyrosinated alpha-tubulin.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Sarcoma	DISZDG3U	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Fibrosarcoma	DISWX7MU	moderate	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[4]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[5]

10 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 Tubulin--tyrosine ligase (TTL).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tubulin--tyrosine ligase (TTL).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tubulin--tyrosine ligase (TTL).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tubulin--tyrosine ligase (TTL).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tubulin--tyrosine ligase (TTL).	[10]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Tubulin--tyrosine ligase (TTL).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Tubulin--tyrosine ligase (TTL).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tubulin--tyrosine ligase (TTL).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Tubulin--tyrosine ligase (TTL).	[14]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Tubulin--tyrosine ligase (TTL).	[15]

References

• [1] Suppression of tubulin tyrosine ligase during tumor growth.J Cell Sci. 1998 Jan;111 ( Pt 2):171-81. doi: 10.1242/jcs.111.2.171.
• [2] The sum of gains and losses of genes encoding the protein tyrosine kinase targets predicts response to multi-kinase inhibitor treatment: Characterization, validation, and prognostic value.Oncotarget. 2015 Sep 22;6(28):26388-99. doi: 10.18632/oncotarget.4557.
• [3] Potential role of tubulin tyrosine ligase-like enzymes in tumorigenesis and cancer cell resistance.Cancer Lett. 2014 Aug 1;350(1-2):1-4. doi: 10.1016/j.canlet.2014.04.022. Epub 2014 May 6.
• [4] Identifying tumor promoting genomic alterations in tumor-associated fibroblasts via retrovirus-insertional mutagenesis.Oncotarget. 2017 Oct 16;8(57):97231-97245. doi: 10.18632/oncotarget.21881. eCollection 2017 Nov 14.
• [5] Low expression of human tubulin tyrosine ligase and suppressed tubulin tyrosination/detyrosination cycle are associated with impaired neuronal differentiation in neuroblastomas with poor prognosis.Int J Cancer. 2004 Nov 10;112(3):365-75. doi: 10.1002/ijc.20431.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [15] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.