Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJQ8RF4)

• DOT Name: Tubulin--tyrosine ligase-like protein 12 (TTLL12)
• Synonyms: Inactive tubulin--tyrosine ligase-like protein 12
• Gene Name: TTLL12
• Related Disease:
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: TTL12_HUMAN
• Pfam ID: PF03133
• Sequence:
  MEAERGPERRPAERSSPGQTPEEGAQALAEFAALHGPALRASGVPERYWGRLLHKLEHEV
  FDAGEVFGIMQVEEVEEEEDEAAREVRKQQPNPGNELCYKVIVTRESGLQAAHPNSIFLI
  DHAWTCRVEHARQQLQQVPGLLHRMANLMGIEFHGELPSTEAVALVLEEMWKFNQTYQLA
  HGTAEEKMPVWYIMDEFGSRIQHADVPSFATAPFFYMPQQVAYTLLWPLRDLDTGEEVTR
  DFAYGETDPLIRKCMLLPWAPTDMLDLSSCTPEPPAEHYQAILEENKEKLPLDINPVVHP
  HGHIFKVYTDVQQVASSLTHPRFTLTQSEADADILFNFSHFKDYRKLSQERPGVLLNQFP
  CENLLTVKDCLASIARRAGGPEGPPWLPRTFNLRTELPQFVSYFQQRERWGEDNHWICKP
  WNLARSLDTHVTKSLHSIIRHRESTPKVVSKYIESPVLFLREDVGKVKFDIRYIVLLRSV
  RPLRLFVYDVFWLRFSNRAFALNDLDDYEKHFTVMNYDPDVVLKQVHCEEFIPEFEKQYP
  EFPWTDVQAEIFRAFTELFQVACAKPPPLGLCDYPSSRAMYAVDLMLKWDNGPDGRRVMQ
  PQILEVNFNPDCERACRYHPTFFNDVFSTLFLDQPGGCHVTCLV
• Function: Negatively regulates post-translational modifications of tubulin, including detyrosination of the C-terminus and polyglutamylation of glutamate residues. Also, indirectly promotes histone H4 trimethylation at 'Lys-20' (H4K20me3). Probably by controlling tubulin and/or histone H4 post-translational modifications, plays a role in mitosis and in maintaining chromosome number stability. During RNA virus-mediated infection, acts as a negative regulator of the RIG-I pathway by preventing MAVS binding to TBK1 and IKBKE.
• Tissue Specificity: Expressed in the basal layer of prostate and endothelial cells. Increased expression in prostatic intraepithelial neoplasia and metastatic lesions.
• 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
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Limited	Biomarker	[2]
Lung carcinoma	DISTR26C	Limited	Biomarker	[2]

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--tyrosine ligase-like protein 12 (TTLL12).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tubulin--tyrosine ligase-like protein 12 (TTLL12).	[14]

References

• [1] Tubulin tyrosine ligase like 12 links to prostate cancer through tubulin posttranslational modification and chromosome ploidy.Int J Cancer. 2010 Dec 1;127(11):2542-53. doi: 10.1002/ijc.25261.
• [2] Identification of a novel transcript isoform of the TTLL12 gene in human cancers.Oncol Rep. 2016 Dec;36(6):3172-3180. doi: 10.3892/or.2016.5135. Epub 2016 Sep 28.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [11] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.