Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCE097J)

• DOT Name: Polyglutamylase complex subunit TTLL1 (TTLL1)
• Synonyms: EC 6.3.2.-; Tubulin polyglutamylase TTLL1; Tubulin polyglutamylase complex subunit 3; PGs3; Tubulin--tyrosine ligase-like protein 1
• Gene Name: TTLL1
• Related Disease:
  Neoplasm
  Advanced cancer
  Fibrosarcoma
  Hepatocellular carcinoma
  Neuroblastoma
• UniProt ID: TTLL1_HUMAN
• EC Number: 6.3.2.-
• Pfam ID: PF03133
• Sequence:
  MAGKVKWVTDIEKSVLINNFEKRGWVQVTENEDWNFYWMSVQTIRNVFSVEAGYRLSDDQ
  IVNHFPNHYELTRKDLMVKNIKRYRKELEKEGSPLAEKDENGKYLYLDFVPVTYMLPADY
  NLFVEEFRKSPSSTWIMKPCGKAQGKGIFLINKLSQIKKWSRDSKTSSFVSQSNKEAYVI
  SLYINNPLLIGGRKFDLRLYVLVSTYRPLRCYMYKLGFCRFCTVKYTPSTSELDNMFVHL
  TNVAIQKHGEDYNHIHGGKWTVSNLRLYLESTRGKEVTSKLFDEIHWIIVQSLKAVAPVM
  NNDKHCFECYGYDIIIDDKLKPWLIEVNASPSLTSSTANDRILKYNLINDTLNIAVPNGE
  IPDCKWNKSPPKEVLGNYEILYDEELAQGDGADRELRSRQGQSLGPRAGRSRDSGRAVLT
  TWK
• Function: Catalytic subunit of a polyglutamylase complex which modifies tubulin, generating side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin. Probably involved in the side-chain elongation step of the polyglutamylation reaction rather than the initiation step. Modifies both alpha- and beta-tubulins with a preference for the alpha-tail. Unlike most polyglutamylases of the tubulin--tyrosine ligase family, only displays a catalytic activity when in complex with other proteins as it is most likely lacking domains important for autonomous activity. Part of the neuronal tubulin polyglutamylase complex. Mediates cilia and flagella polyglutamylation which is essential for their biogenesis and motility. Involved in respiratory motile cilia function through the regulation of beating asymmetry. Essential for sperm flagella biogenesis, motility and male fertility. Involved in KLF4 glutamylation which impedes its ubiquitination, thereby leading to somatic cell reprogramming, pluripotency maintenance and embryogenesis.
• Tissue Specificity: Expressed in a wide range of tissues. Has a stronger expression in heart, brain and testis.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[2]
Fibrosarcoma	DISWX7MU	moderate	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[3]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Polyglutamylase complex subunit TTLL1 (TTLL1).	[12]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [10] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] 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.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.