Details of Drug Off-Target (DOT)

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

• DOT Name: Tubulin beta-1 chain
• Gene Name: TUBB1
• Related Disease:
  Macrothrombocytopenia, isolated, 1, autosomal dominant
  Autosomal dominant macrothrombocytopenia
• UniProt ID: TBB1_HUMAN
• Pfam ID: PF00091 ; PF03953
• Sequence:
  MREIVHIQIGQCGNQIGAKFWEMIGEEHGIDLAGSDRGASALQLERISVYYNEAYGRKYV
  PRAVLVDLEPGTMDSIRSSKLGALFQPDSFVHGNSGAGNNWAKGHYTEGAELIENVLEVV
  RHESESCDCLQGFQIVHSLGGGTGSGMGTLLMNKIREEYPDRIMNSFSVMPSPKVSDTVV
  EPYNAVLSIHQLIENADACFCIDNEALYDICFRTLKLTTPTYGDLNHLVSLTMSGITTSL
  RFPGQLNADLRKLAVNMVPFPRLHFFMPGFAPLTAQGSQQYRALSVAELTQQMFDARNTM
  AACDLRRGRYLTVACIFRGKMSTKEVDQQLLSVQTRNSSCFVEWIPNNVKVAVCDIPPRG
  LSMAATFIGNNTAIQEIFNRVSEHFSAMFKRKAFVHWYTSEGMDINEFGEAENNIHDLVS
  EYQQFQDAKAVLEEDEEVTEEAEMEPEDKGH
• 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.
• Tissue Specificity: Hematopoietic cell-specific. Major isotype in leukocytes, where it represents 50% of all beta-tubulins.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Macrothrombocytopenia, isolated, 1, autosomal dominant	DISS1YOK	Definitive	Autosomal dominant	[1]
Autosomal dominant macrothrombocytopenia	DISUTMSW	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PEITC	DMOMN31	Phase 2	Tubulin beta-1 chain affects the binding of PEITC.	[19]
Sulforaphane	DMQY3L0	Investigative	Tubulin beta-1 chain affects the binding of Sulforaphane.	[19]

3 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-1 chain.	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tubulin beta-1 chain.	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tubulin beta-1 chain.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tubulin beta-1 chain.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tubulin beta-1 chain.	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tubulin beta-1 chain.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tubulin beta-1 chain.	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tubulin beta-1 chain.	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tubulin beta-1 chain.	[9]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Tubulin beta-1 chain.	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Tubulin beta-1 chain.	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Tubulin beta-1 chain.	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Tubulin beta-1 chain.	[13]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Tubulin beta-1 chain.	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tubulin beta-1 chain.	[14]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Tubulin beta-1 chain.	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tubulin beta-1 chain.	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tubulin beta-1 chain.	[16]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Tubulin beta-1 chain.	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Tubulin beta-1 chain.	[18]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE affects the expression of Tubulin beta-1 chain.	[8]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Tubulin beta-1 chain.	[13]

References

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• [2] Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly. Blood. 2009 Jan 8;113(2):458-61. doi: 10.1182/blood-2008-06-162610. Epub 2008 Oct 10.
• [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.
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• [5] 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.
• [6] 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.
• [7] 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.
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• [9] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity (Silver Spring). 2010 Jan;18(1):27-34. doi: 10.1038/oby.2009.208. Epub 2009 Jun 25.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [19] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.