Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1M1SZH)

• DOT Name: Probable tubulin polyglutamylase TTLL9 (TTLL9)
• Synonyms: EC 6.3.2.-; Tubulin--tyrosine ligase-like protein 9
• Gene Name: TTLL9
• Related Disease:
  Liver cancer
  Polycystic ovarian syndrome
  Precancerous condition
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
• UniProt ID: TTLL9_HUMAN
• EC Number: 6.3.2.-
• Pfam ID: PF03133
• Sequence:
  MVPSREALLGPGTTAIRCPKKLQNQNYKGHGLSKGKEREQRASIRFKTTLMNTLMDVLRH
  RPGWVEVKDEGEWDFYWCDVSWLRENFDHTYMDEHVRISHFRNHYELTRKNYMVKNLKRF
  RKQLEREAGKLEAAKCDFFPKTFEMPCEYHLFVEEFRKNPGITWIMKPVARSQGKGIFLF
  RRLKDIVDWRKDTRSSDDQKDDIPVENYVAQRYIENPYLIGGRKFDLRVYVLVMSVFAEC
  LLWSGHRRQDVHLTNVAVQKTSPDYHPKKGCKWTLQRFRQYLASKHGPEAVETLFRDIDN
  IFVKSLQSVQKVIISDKHCFELYGYDILIDQDLKPWLLEVNASPSLTASSQEDYELKTCL
  LEDTLHVVDMEARLTGREKRVGGFDLMWNDGPVSREEGAPDLSGMGNFVTNTHLGCVNDR
  KKQLRQLFCSLQVQKKASS
• Function: Probable tubulin polyglutamylase that generates side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of target proteins. Similar to TTLL1, may acquire enzymatic activity only in complex with other proteins as it is most likely lacking domains important for autonomous activity. Mediates tubulin polyglutamylation which induces establishment of microtubule heterogeneity in sperm flagella, thereby playing a role in normal motile flagella axoneme structure and sperm flagella beating pattern.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Liver cancer	DISDE4BI	Strong	Biomarker	[1]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[2]
Precancerous condition	DISV06FL	Strong	Biomarker	[1]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Moderate	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Probable tubulin polyglutamylase TTLL9 (TTLL9).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Probable tubulin polyglutamylase TTLL9 (TTLL9).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Probable tubulin polyglutamylase TTLL9 (TTLL9).	[6]

References

• [1] Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.Toxicol Sci. 2009 Apr;108(2):273-89. doi: 10.1093/toxsci/kfp031. Epub 2009 Feb 20.
• [2] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [3] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [4] 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.
• [5] 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.
• [6] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.