Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF8P01M)

• DOT Name: Tubulin polyglutamylase TTLL7 (TTLL7)
• Synonyms: EC 6.3.2.-; Testis development protein NYD-SP30; Tubulin--tyrosine ligase-like protein 7
• Gene Name: TTLL7
• UniProt ID: TTLL7_HUMAN
• PDB ID: 4YLR; 4YLS
• EC Number: 6.3.2.-
• Pfam ID: PF03133
• Sequence:
  MPSLPQEGVIQGPSPLDLNTELPYQSTMKRKVRKKKKKGTITANVAGTKFEIVRLVIDEM
  GFMKTPDEDETSNLIWCDSAVQQEKISELQNYQRINHFPGMGEICRKDFLARNMTKMIKS
  RPLDYTFVPRTWIFPAEYTQFQNYVKELKKKRKQKTFIVKPANGAMGHGISLIRNGDKLP
  SQDHLIVQEYIEKPFLMEGYKFDLRIYILVTSCDPLKIFLYHDGLVRMGTEKYIPPNESN
  LTQLYMHLTNYSVNKHNEHFERDETENKGSKRSIKWFTEFLQANQHDVAKFWSDISELVV
  KTLIVAEPHVLHAYRMCRPGQPPGSESVCFEVLGFDILLDRKLKPWLLEINRAPSFGTDQ
  KIDYDVKRGVLLNALKLLNIRTSDKRRNLAKQKAEAQRRLYGQNSIKRLLPGSSDWEQQR
  HQLERRKEELKERLAQVRKQISREEHENRHMGNYRRIYPPEDKALLEKYENLLAVAFQTF
  LSGRAASFQRELNNPLKRMKEEDILDLLEQCEIDDEKLMGKTTKTRGPKPLCSMPESTEI
  MKRPKYCSSDSSYDSSSSSSESDENEKEEYQNKKREKQVTYNLKPSNHYKLIQQPSSIRR
  SVSCPRSISAQSPSSGDTRPFSAQQMISVSRPTSASRSHSLNRASSYMRHLPHSNDACST
  NSQVSESLRQLKTKEQEDDLTSQTLFVLKDMKIRFPGKSDAESELLIEDIIDNWKYHKTK
  VASYWLIKLDSVKQRKVLDIVKTSIRTVLPRIWKVPDVEEVNLYRIFNRVFNRLLWSRGQ
  GLWNCFCDSGSSWESIFNKSPEVVTPLQLQCCQRLVELCKQCLLVVYKYATDKRGSLSGI
  GPDWGNSRYLLPGSTQFFLRTPTYNLKYNSPGMTRSNVLFTSRYGHL
• Function: Polyglutamylase which modifies tubulin, generating polyglutamate side chains of variable lengths on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin. Mediates both ATP-dependent initiation and elongation steps of the polyglutamylation reaction. Preferentially modifies the beta-tubulin tail over an alpha-tail. Competes with monoglycylase TTLL3 for modification site on beta-tubulin substrate, thereby creating an anticorrelation between glycylation and glutamylation reactions. Required for neurite growth; responsible for the strong increase in tubulin polyglutamylation during postnatal neuronal maturation.
• Tissue Specificity: Highly expressed in the nervous system including spinal cord, thalamus, hippocampus, hypothalamus and cerebellum.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

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 polyglutamylase TTLL7 (TTLL7).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[10]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Tubulin polyglutamylase TTLL7 (TTLL7).	[11]

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 polyglutamylase TTLL7 (TTLL7).	[8]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [4] 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.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [10] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [11] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.