Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ2OTQT)

• DOT Name: Tubulin beta-2B chain
• Gene Name: TUBB2B
• Related Disease:
  Complex cortical dysplasia with other brain malformations
  Complex cortical dysplasia with other brain malformations 7
  Cerebellar ataxia, intellectual disability, and dysequilibrium
  Congenital fibrosis of extraocular muscles
  Tubulinopathy-associated dysgyria
• UniProt ID: TBB2B_HUMAN
• PDB ID: 6E7C; 7ZCW
• Pfam ID: PF00091 ; PF03953
• Sequence:
  MREIVHIQAGQCGNQIGAKFWEVISDEHGIDPTGSYHGDSDLQLERINVYYNEATGNKYV
  PRAILVDLEPGTMDSVRSGPFGQIFRPDNFVFGQSGAGNNWAKGHYTEGAELVDSVLDVV
  RKESESCDCLQGFQLTHSLGGGTGSGMGTLLISKIREEYPDRIMNTFSVMPSPKVSDTVV
  EPYNATLSVHQLVENTDETYCIDNEALYDICFRTLKLTTPTYGDLNHLVSATMSGVTTCL
  RFPGQLNADLRKLAVNMVPFPRLHFFMPGFAPLTSRGSQQYRALTVPELTQQMFDSKNMM
  AACDPRHGRYLTVAAIFRGRMSMKEVDEQMLNVQNKNSSYFVEWIPNNVKTAVCDIPPRG
  LKMSATFIGNSTAIQELFKRISEQFTAMFRRKAFLHWYTGEGMDEMEFTEAESNMNDLVS
  EYQQYQDATADEQGEFEEEEGEDEA
• Function: Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers. Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms. Below the cap, tubulin dimers are in GDP-bound state, owing to GTPase activity of alpha-tubulin. Plays a critical role in proper axon guidance in both central and peripheral axon tracts. Implicated in neuronal migration.
• Tissue Specificity: High expression in brain.
• KEGG Pathway:
  Phagosome (hsa04145)
  Gap junction (hsa04540)
  Motor proteins (hsa04814)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane (R-HSA-190840)
  Gap junction assembly (R-HSA-190861)
  MHC class II antigen presentation (R-HSA-2132295)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Prefoldin mediated transfer of substrate to CCT/TriC (R-HSA-389957)
  Formation of tubulin folding intermediates by CCT/TriC (R-HSA-389960)
  Post-chaperonin tubulin folding pathway (R-HSA-389977)
  Recycling pathway of L1 (R-HSA-437239)
  Hedgehog 'off' state (R-HSA-5610787)
  Cilium Assembly (R-HSA-5617833)
  Intraflagellar transport (R-HSA-5620924)
  RHO GTPases activate IQGAPs (R-HSA-5626467)
  RHO GTPases Activate Formins (R-HSA-5663220)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Mitotic Prometaphase (R-HSA-68877)
  The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276)
  Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)
  HCMV Early Events (R-HSA-9609690)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Activation of AMPK downstream of NMDARs (R-HSA-9619483)
  Aggrephagy (R-HSA-9646399)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)
  Kinesins (R-HSA-983189)
  PKR-mediated signaling (R-HSA-9833482)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex cortical dysplasia with other brain malformations	DISTLV37	Definitive	Autosomal dominant	[1]
Complex cortical dysplasia with other brain malformations 7	DISAG0MM	Definitive	Autosomal dominant	[2]
Cerebellar ataxia, intellectual disability, and dysequilibrium	DIS9923V	Supportive	Autosomal recessive	[3]
Congenital fibrosis of extraocular muscles	DISE84PU	Supportive	Autosomal dominant	[4]
Tubulinopathy-associated dysgyria	DISXIWVG	Supportive	Autosomal dominant	[5]

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 beta-2B chain.	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tubulin beta-2B chain.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tubulin beta-2B chain.	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tubulin beta-2B chain.	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tubulin beta-2B chain.	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tubulin beta-2B chain.	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tubulin beta-2B chain.	[11]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Tubulin beta-2B chain.	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tubulin beta-2B chain.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tubulin beta-2B chain.	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tubulin beta-2B chain.	[14]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Tubulin beta-2B chain.	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Tubulin beta-2B chain.	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Tubulin beta-2B chain.	[8]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Tubulin beta-2B chain.	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Tubulin beta-2B chain.	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tubulin beta-2B chain.	[20]

References

• [1] 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.
• [2] Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat Genet. 2009 Jun;41(6):746-52. doi: 10.1038/ng.380. Epub 2009 May 24.
• [3] Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability. Hum Mol Genet. 2017 Jan 15;26(2):258-269. doi: 10.1093/hmg/ddw383.
• [4] An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation. Hum Mol Genet. 2012 Dec 15;21(26):5484-99. doi: 10.1093/hmg/dds393. Epub 2012 Sep 21.
• [5] Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes. Hum Mol Genet. 2015 Sep 15;24(18):5313-25. doi: 10.1093/hmg/ddv250. Epub 2015 Jun 30.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.
• [12] Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics. Toxicol Appl Pharmacol. 2010 Jan 15;242(2):126-35. doi: 10.1016/j.taap.2009.09.016. Epub 2009 Oct 7.
• [13] 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.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] 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.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.