Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHBM3DX)

DOT Name Tubulin polyglutamylase TTLL6 (TTLL6)
Synonyms EC 6.3.2.-; Protein polyglutamylase TTLL6; Tubulin--tyrosine ligase-like protein 6
Gene Name TTLL6
Related Disease
Non-insulin dependent diabetes ( )
Bipolar disorder ( )
Mental disorder ( )
Psychotic disorder ( )
Schizophrenia ( )
UniProt ID
TTLL6_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
6.3.2.-
Pfam ID
PF03133
Sequence
MGALLLHPSRRGPAGVVASWTSSPAGRDGGVGIAGAWYFPRASSQAREMPQCPTLESQEG
ENSEEKGDSSKEDPKETVALAFVRENPGAQNGLQNAQQQGKKKRKKKRLVINLSSCRYES
VRRAAQQYGFREGGEDDDWTLYWTDYSVSLERVMEMKSYQKINHFPGMSEICRKDLLARN
MSRMLKMFPKDFRFFPRTWCLPADWGDLQTYSRSRKNKTYICKPDSGCQGKGIFITRTVK
EIKPGEDMICQLYISKPFIIDGFKFDLRIYVLVTSCDPLRIFVYNEGLARFATTSYSRPC
TDNLDDICMHLTNYSINKHSSNFSRDAHSGSKRKLSTFSAYLEDHSYNVEQIWRDIEDVI
IKTLISAHPIIRHNYHTCFPNHTLNSACFEILGFDILLDHKLKPWLLEVNHSPSFSTDSR
LDKEVKDGLLYDTLVLINLESCDKKKVLEEERQRGQFLQQCCSREMRIEEAKGFRAVQLK
KTETYEKENCGGFRLIYPSLNSEKYEKFFQDNNSLFQNTVASRAREEYARQLIQELRLKR
EKKPFQMKKKVEMQGESAGEQVRKKGMRGWQQKQQQKDKAATQASKQYIQPLTLVSYTPD
LLLSVRGERKNETDSSLNQEAPTEEASSVFPKLTSAKPFSSLPDLRNINLSSSKLEPSKP
NFSIKEAKSASAVNVFTGTVHLTSVETTPESTTQLSISPKSPPTLAVTASSEYSGPETDR
VVSFKCKKQQTPPHLTQKKMLKSFLPTKSKSFWESPNTNWTLLKSDMNKPHLISELLTKL
QLSGKLSFFPAHYNPKLGMNNLSQNPSLPGECHSRSDSSGEKRQLDVSSLLLQSPQSYNV
TLRDLLVIATPAQLDPRPCRSHASAMRDPCMQDQEAYSHCLISGQKGCERS
Function
Polyglutamylase which modifies both tubulin and non-tubulin proteins, generating alpha-linked polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues of target proteins. Preferentially mediates ATP-dependent long polyglutamate chain elongation over the initiation step of the polyglutamylation reaction. Preferentially modifies the alpha-tubulin tail over a beta-tail. Promotes tubulin polyglutamylation which stimulates spastin/SPAST-mediated microtubule severing, thereby regulating microtubule functions. Mediates microtubule polyglutamylation in primary cilia axoneme, which is important for ciliary structural formation and motility. Mediates microtubule polyglutamylation in motile cilia, necessary for the regulation of ciliary coordinated beating. Polyglutamylates non-tubulin protein nucleotidyltransferase CGAS, leading to CGAS DNA-binding inhibition, thereby preventing antiviral defense response.
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
Non-insulin dependent diabetes DISK1O5Z Strong Genetic Variation [1]
Bipolar disorder DISAM7J2 Limited Genetic Variation [2]
Mental disorder DIS3J5R8 Limited Genetic Variation [2]
Psychotic disorder DIS4UQOT Limited Genetic Variation [2]
Schizophrenia DISSRV2N Limited Genetic Variation [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of Tubulin polyglutamylase TTLL6 (TTLL6). [3]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Tubulin polyglutamylase TTLL6 (TTLL6). [6]
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3 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Tubulin polyglutamylase TTLL6 (TTLL6). [4]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Tubulin polyglutamylase TTLL6 (TTLL6). [5]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Tubulin polyglutamylase TTLL6 (TTLL6). [7]
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References

1 Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes.Mol Metab. 2019 Jun;24:98-107. doi: 10.1016/j.molmet.2019.03.004. Epub 2019 Mar 18.
2 Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia.Mol Psychiatry. 2014 Sep;19(9):1017-1024. doi: 10.1038/mp.2013.138. Epub 2013 Nov 26.
3 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
4 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
5 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
6 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.
7 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.