Details of Drug Off-Target (DOT)

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

• DOT Name: Tubulin monoglutamylase TTLL4 (TTLL4)
• Synonyms: EC 6.3.2.-; Protein monoglutamylase TTLL4; Tubulin--tyrosine ligase-like protein 4
• Gene Name: TTLL4
• Related Disease:
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: TTLL4_HUMAN
• PDB ID: 5T6X
• EC Number: 6.3.2.-
• Pfam ID: PF03133
• Sequence:
  MASAGTQHYSIGLRQKNSFKQSGPSGTVPATPPEKPSEGRVWPQAHQQVKPIWKLEKKQV
  ETLSAGLGPGLLGVPPQPAYFFCPSTLCSSGTTAVIAGHSSSCYLHSLPDLFNSTLLYRR
  SSYRQKPYQQLESFCLRSSPSEKSPFSLPQKSLPVSLTANKATSSMVFSMAQPMASSSTE
  PYLCLAAAGENPSGKSLASAISGKIPSPLSSSYKPMLNNNSFMWPNSTPVPLLQTTQGLK
  PVSPPKIQPVSWHHSGGTGDCAPQPVDHKVPKSIGTVPADASAHIALSTASSHDTSTTSV
  ASSWYNRNNLAMRAEPLSCALDDSSDSQDPTKEIRFTEAVRKLTARGFEKMPRQGCQLEQ
  SSFLNPSFQWNVLNRSRRWKPPAVNQQFPQEDAGSVRRVLPGASDTLGLDNTVFCTKRIS
  IHLLASHASGLNHNPACESVIDSSAFGEGKAPGPPFPQTLGIANVATRLSSIQLGQSEKE
  RPEEARELDSSDRDISSATDLQPDQAETEDTEEELVDGLEDCCSRDENEEEEGDSECSSL
  SAVSPSESVAMISRSCMEILTKPLSNHEKVVRPALIYSLFPNVPPTIYFGTRDERVEKLP
  WEQRKLLRWKMSTVTPNIVKQTIGRSHFKISKRNDDWLGCWGHHMKSPSFRSIREHQKLN
  HFPGSFQIGRKDRLWRNLSRMQSRFGKKEFSFFPQSFILPQDAKLLRKAWESSSRQKWIV
  KPPASARGIGIQVIHKWSQLPKRRPLLVQRYLHKPYLISGSKFDLRIYVYVTSYDPLRIY
  LFSDGLVRFASCKYSPSMKSLGNKFMHLTNYSVNKKNAEYQANADEMACQGHKWALKALW
  NYLSQKGVNSDAIWEKIKDVVVKTIISSEPYVTSLLKMYVRRPYSCHELFGFDIMLDENL
  KPWVLEVNISPSLHSSSPLDISIKGQMIRDLLNLAGFVLPNAEDIISSPSSCSSSTTSLP
  TSPGDKCRMAPEHVTAQKMKKAYYLTQKIPDQDFYASVLDVLTPDDVRILVEMEDEFSRR
  GQFERIFPSHISSRYLRFFEQPRYFNILTTQWEQKYHGNKLKGVDLLRSWCYKGFHMGVV
  SDSAPVWSLPTSLLTISKDDVILNAFSKSETSKLGKQSSCEVSLLLSEDGTTPKSKKTQA
  GLSPYPQKPSSSKDSEDTSKEPSLSTQTLPVIKCSGQTSRLSASSTFQSISDSLLAVSP
• Function: Monoglutamylase which modifies both tubulin and non-tubulin proteins, adding a single glutamate on the gamma-carboxyl group of specific glutamate residues of target proteins. Involved in the side-chain initiation step of the polyglutamylation reaction but not in the elongation step. Preferentially modifies beta-tail tubulin over the alpha-tubulin. Monoglutamylates nucleosome assembly proteins NAP1L1 and NAP1L4. Monoglutamylates nucleotidyltransferase CGAS, leading to inhibition of CGAS catalytic activity, thereby preventing antiviral defense function. Involved in KLF4 glutamylation which impedes its ubiquitination, thereby leading to somatic cell reprogramming, pluripotency maintenance and embryogenesis.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[1]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[1]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[1]

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 Tubulin monoglutamylase TTLL4 (TTLL4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tubulin monoglutamylase TTLL4 (TTLL4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tubulin monoglutamylase TTLL4 (TTLL4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tubulin monoglutamylase TTLL4 (TTLL4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tubulin monoglutamylase TTLL4 (TTLL4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tubulin monoglutamylase TTLL4 (TTLL4).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tubulin monoglutamylase TTLL4 (TTLL4).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tubulin monoglutamylase TTLL4 (TTLL4).	[11]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Tubulin monoglutamylase TTLL4 (TTLL4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Tubulin monoglutamylase TTLL4 (TTLL4).	[10]

References

• [1] Involvement of the tubulin tyrosine ligase-like family member 4 polyglutamylase in PELP1 polyglutamylation and chromatin remodeling in pancreatic cancer cells.Cancer Res. 2010 May 15;70(10):4024-33. doi: 10.1158/0008-5472.CAN-09-4444. Epub 2010 May 4.
• [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] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.