Details of Drug Off-Target (DOT)

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

• DOT Name: Tubulin polyglutamylase TTLL5 (TTLL5)
• Synonyms: EC 6.3.2.-; SRC1 and TIF2-associated modulatory protein; STAMP protein; Tubulin--tyrosine ligase-like protein 5
• Gene Name: TTLL5
• Related Disease:
  Cone-rod dystrophy 19
  Inherited retinal dystrophy
  Advanced cancer
  Cone dystrophy
  Crohn disease
  Juvenile idiopathic arthritis
  Acute myelogenous leukaemia
  Retinopathy
  Cone-rod dystrophy
  Anxiety
  Anxiety disorder
  Cone-rod dystrophy 2
  Carpal tunnel syndrome
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: TTLL5_HUMAN
• EC Number: 6.3.2.-
• Pfam ID: PF03133
• Sequence:
  MPIVMARDLEETASSSEDEEVISQEDHPCIMWTGGCRRIPVLVFHADAILTKDNNIRVIG
  ERYHLSYKIVRTDSRLVRSILTAHGFHEVHPSSTDYNLMWTGSHLKPFLLRTLSEAQKVN
  HFPRSYELTRKDRLYKNIIRMQHTHGFKAFHILPQTFLLPAEYAEFCNSYSKDRGPWIVK
  PVASSRGRGVYLINNPNQISLEENILVSRYINNPLLIDDFKFDVRLYVLVTSYDPLVIYL
  YEEGLARFATVRYDQGAKNIRNQFMHLTNYSVNKKSGDYVSCDDPEVEDYGNKWSMSAML
  RYLKQEGRDTTALMAHVEDLIIKTIISAELAIATACKTFVPHRSSCFELYGFDVLIDSTL
  KPWLLEVNLSPSLACDAPLDLKIKASMISDMFTVVGFVCQDPAQRASTRPIYPTFESSRR
  NPFQKPQRCRPLSASDAEMKNLVGSAREKGPGKLGGSVLGLSMEEIKVLRRVKEENDRRG
  GFIRIFPTSETWEIYGSYLEHKTSMNYMLATRLFQDRMTADGAPELKIESLNSKAKLHAA
  LYERKLLSLEVRKRRRRSSRLRAMRPKYPVITQPAEMNVKTETESEEEEEVALDNEDEEQ
  EASQEESAGFLRENQAKYTPSLTALVENTPKENSMKVREWNNKGGHCCKLETQELEPKFN
  LMQILQDNGNLSKMQARIAFSAYLQHVQIRLMKDSGGQTFSASWAAKEDEQMELVVRFLK
  RASNNLQHSLRMVLPSRRLALLERRRILAHQLGDFIIVYNKETEQMAEKKSKKKVEEEEE
  DGVNMENFQEFIRQASEAELEEVLTFYTQKNKSASVFLGTHSKISKNNNNYSDSGAKGDH
  PETIMEEVKIKPPKQQQTTEIHSDKLSRFTTSAEKEAKLVYSNSSSGPTATLQKIPNTHL
  SSVTTSDLSPGPCHHSSLSQIPSAIPSMPHQPTILLNTVSASASPCLHPGAQNIPSPTGL
  PRCRSGSHTIGPFSSFQSAAHIYSQKLSRPSSAKAGSCYLNKHHSGIAKTQKEGEDASLY
  SKRYNQSMVTAELQRLAEKQAARQYSPSSHINLLTQQVTNLNLATGIINRSSASAPPTLR
  PIISPSGPTWSTQSDPQAPENHSSSPGSRSLQTGGFAWEGEVENNVYSQATGVVPQHKYH
  PTAGSYQLQFALQQLEQQKLQSRQLLDQSRARHQAIFGSQTLPNSNLWTMNNGAGCRISS
  ATASGQKPTTLPQKVVPPPSSCASLVPKPPPNHEQVLRRATSQKASKGSSAEGQLNGLQS
  SLNPAAFVPITSSTDPAHTKI
• Function: Polyglutamylase which modifies tubulin, generating polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin. Preferentially mediates ATP-dependent initiation step of the polyglutamylation reaction over the elongation step. Preferentially modifies the alpha-tubulin tail over a beta-tail. Required for CCSAP localization to both polyglutamylated spindle and cilia microtubules. Increases the effects of transcriptional coactivator NCOA2/TIF2 in glucocorticoid receptor-mediated repression and induction and in androgen receptor-mediated induction.
• Tissue Specificity: Expressed in the retina, found in the rod and cone photoreceptors (at protein level). Widely expressed with highest levels in heart and skeletal muscle and low levels in other tissues.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy 19	DIS3A1IS	Definitive	Autosomal recessive	[1]
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Cone dystrophy	DIS7SAZZ	Strong	Genetic Variation	[4]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[5]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[6]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[7]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[8]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[1]
Anxiety	DISIJDBA	Disputed	Biomarker	[9]
Anxiety disorder	DISBI2BT	Disputed	Biomarker	[9]
Cone-rod dystrophy 2	DISX2RWY	Disputed	GermlineCausalMutation	[1]
Carpal tunnel syndrome	DISHQ3BE	Limited	Genetic Variation	[10]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[3]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[3]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tubulin polyglutamylase TTLL5 (TTLL5).	[17]

References

• [1] Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy. Am J Hum Genet. 2014 May 1;94(5):760-9. doi: 10.1016/j.ajhg.2014.04.003.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] STAMP alters the growth of transformed and ovarian cancer cells.BMC Cancer. 2010 Apr 7;10:128. doi: 10.1186/1471-2407-10-128.
• [4] Novel splice-site mutation in TTLL5 causes cone dystrophy in a consanguineous family.Mol Vis. 2017 Mar 18;23:131-139. eCollection 2017.
• [5] Gut Microbial Signatures Underline Complicated Crohn's Disease but Vary Between Cohorts; An In Silico Approach.Inflamm Bowel Dis. 2019 Jan 10;25(2):217-225. doi: 10.1093/ibd/izy328.
• [6] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [7] 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.
• [8] Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility.Hum Mol Genet. 2016 Oct 15;25(20):4546-4555. doi: 10.1093/hmg/ddw282.
• [9] Effects of anxiety sensitivity reduction on smoking abstinence: An analysis from a panic prevention program.J Consult Clin Psychol. 2018 May;86(5):474-485. doi: 10.1037/ccp0000288.
• [10] A genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome.Nat Commun. 2019 Mar 4;10(1):1030. doi: 10.1038/s41467-019-08993-6.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] 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.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] 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.
• [16] 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.
• [17] 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.