Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7JWXHA)

• DOT Name: Tubulin monoglycylase TTLL3 (TTLL3)
• Synonyms: EC 6.3.2.-; HOTTL; Tubulin--tyrosine ligase-like protein 3
• Gene Name: TTLL3
• Related Disease:
  Colorectal carcinoma
  Neoplasm
• UniProt ID: TTLL3_HUMAN
• EC Number: 6.3.2.-
• Pfam ID: PF03133
• Sequence:
  MNRLRNAKIYVERAVKQKKIFTIQGCYPVIRCLLRRRGWVEKKMVHRSGPTLLPPQKDLD
  SSAMGDSDTTEDEDEDEDEEFQPSQLFDFDDLLKFDDLDGTHALMVGLCLNLRNLPWFDE
  VDANSFFPRCYCLGAEDDKKAFIEDFWLTAARNVLKLVVKSEWKSYPIQAVEEEASGDKQ
  PKKQEKNPVLVSPEFVDEALCACEEYLSNLAHMDIDKDLEAPLYLTPEGWSLFLQRYYQV
  VHEGAELRHLDTQVQRCEDILQQLQAVVPQIDMEGDRNIWIVKPGAKSRGRGIMCMDHLE
  EMLKLVNGNPVVMKDGKWVVQKYIERPLLIFGTKFDLRQWFLVTDWNPLTVWFYRDSYIR
  FSTQPFSLKNLDNSVHLCNNSIQKHLENSCHRHPLLPPDNMWSSQRFQAHLQEMGAPNAW
  STIIVPGMKDAVIHALQTSQDTVQCRKASFELYGADFVFGEDFQPWLIEINASPTMAPST
  AVTARLCAGVQADTLRVVIDRMLDRNCDTGAFELIYKQPAVEVPQYVGIRLLVEGFTIKK
  PMAMCHRRMGVRPAVPLLTQRGSGEARHHFPSLHTKAQLPSPHVLRHQGQVLRRQHSKLV
  GTKALSTTGKALRTLPTAKVFISLPPNLDFKVAPSILKPRKAPALLCLRGPQLEVPCCLC
  PLKSEQFLAPVGRSRPKANSRPDCDKPRAEACPMKRLSPLKPLPLVGTFQRRRGLGDMKL
  GKPLLRFPTALVLDPTPNKKKQVKYLGLDSIAVGGSRVDGARPCTPGSTARA
• Function: Monoglycylase which modifies alpha- and beta-tubulin, adding a single glycine on the gamma-carboxyl groups of specific glutamate residues to generate monoglycine side chains within the C-terminal tail of tubulin. Not involved in elongation step of the polyglycylation reaction. Preferentially glycylates a beta-tail peptide over the alpha-tail, although shifts its preference toward alpha-tail as beta-tail glutamylation increases. Competes with polyglutamylases for modification site on beta-tubulin substrate, thereby creating an anticorrelation between glycylation and glutamylation reactions. Together with TTLL8, mediates microtubule glycylation of primary and motile cilia, which is essential for their stability and maintenance. Involved in microtubule glycylation of primary cilia in colon which controls cell proliferation of epithelial cells and plays an essential role in colon cancer development. Together with TTLL8, glycylates sperm flagella which regulates axonemal dynein motor activity, thereby controlling flagellar beat, directional sperm swimming and male fertility.
• Tissue Specificity: Expressed in brain, heart, kidney, testis, liver, lung, muscle, spleen, trachea and colon.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

7 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 Tubulin monoglycylase TTLL3 (TTLL3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tubulin monoglycylase TTLL3 (TTLL3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tubulin monoglycylase TTLL3 (TTLL3).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tubulin monoglycylase TTLL3 (TTLL3).	[5]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Tubulin monoglycylase TTLL3 (TTLL3).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Tubulin monoglycylase TTLL3 (TTLL3).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tubulin monoglycylase TTLL3 (TTLL3).	[9]

1 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 increases the methylation of Tubulin monoglycylase TTLL3 (TTLL3).	[8]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 affects the binding of Tubulin monoglycylase TTLL3 (TTLL3).	[10]

References

• [1] Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon.EMBO J. 2014 Oct 1;33(19):2247-60. doi: 10.15252/embj.201488466. Epub 2014 Sep 1.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] 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.
• [9] 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.
• [10] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.