Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWXLE1J)

• DOT Name: Tubulin polyglutamylase TTLL11 (TTLL11)
• Synonyms: EC 6.3.2.-; Tubulin--tyrosine ligase-like protein 11
• Gene Name: TTLL11
• Related Disease:
  Schizophrenia
  Acute myelogenous leukaemia
• UniProt ID: TTL11_HUMAN
• EC Number: 6.3.2.-
• Pfam ID: PF03133
• Sequence:
  MRRGSSESELAARWEAEAVAAAKAAAKAEAEATAETVAEQVRVDAGAAGEPECKAGEEQP
  KVLAPAPAQPSAAEEGNTQVLQRPPPTLPPSKPKPVQGLCPHGKPRDKGRSCKRSSGHGS
  GENGSQRPVTVDSSKARTSLDALKISIRQLKWKEFPFGRRLPCDIYWHGVSFHDNDIFSG
  QVNKFPGMTEMVRKITLSRAVRTMQNLFPEEYNFYPRSWILPDEFQLFVAQVQMVKDDDP
  SWKPTFIVKPDGGCQGDGIYLIKDPSDIRLAGTLQSRPAVVQEYICKPLLIDKLKFDIRL
  YVLLKSLDPLEIYIAKDGLSRFCTEPYQEPTPKNLHRIFMHLTNYSLNIHSGNFIHSDSA
  STGSKRTFSSILCRLSSKGVDIKKVWSDIISVVIKTVIALTPELKVFYQSDIPTGRPGPT
  CFQILGFDILLMKNLKPILLEVNANPSMRIEHEHELSPGVFENVPSLVDEEVKVAVIRDT
  LRLMDPLKKKRENQSQQLEKPFAGKEDALDGELTSAPDCNANPEAHLPSICLKQVFPKYA
  KQFNYLRLVDRMANLFIRFLGIKGTMKLGPTGFRTFIRSCKLSSSSLSMAAVDILYIDIT
  RRWNSMTLDQRDSGMCLQAFVEAFFFLAQRKFKMLPLHEQVASLIDLCEYHLSLLDEKRL
  VCGRGVPSGGRPPHRGPPQEPSPSAQPAGDNPPPRTSCANKLSHPRHTLS
• 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. Preferentially mediates ATP-dependent polyglutamate long side-chain elongation over the initiation step of the polyglutamylation reaction. Preferentially modifies the alpha-tubulin tail over a beta-tail. Required for CCSAP localization to both spindle and cilia microtubules. Promotes tubulin polyglutamylation which stimulates spastin/SPAST-mediated microtubule severing, thereby regulating microtubule functions.
• 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
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[2]

8 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 TTLL11 (TTLL11).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tubulin polyglutamylase TTLL11 (TTLL11).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tubulin polyglutamylase TTLL11 (TTLL11).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tubulin polyglutamylase TTLL11 (TTLL11).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tubulin polyglutamylase TTLL11 (TTLL11).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tubulin polyglutamylase TTLL11 (TTLL11).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tubulin polyglutamylase TTLL11 (TTLL11).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tubulin polyglutamylase TTLL11 (TTLL11).	[10]

References

• [1] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [2] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [10] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.