Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7CLZKS)

• DOT Name: Katanin p80 WD40 repeat-containing subunit B1 (KATNB1)
• Synonyms: Katanin p80 subunit B1; p80 katanin
• Gene Name: KATNB1
• Related Disease:
  Holoprosencephaly
  Lissencephaly 6 with microcephaly
  Acute myelogenous leukaemia
  Carcinoma
  Isolated congenital microcephaly
  Isolated growth hormone deficiency type IA
  Lissencephaly spectrum disorders
  Neoplasm
  Oligospermia
  Schizophrenia
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Microlissencephaly
• UniProt ID: KTNB1_HUMAN
• Pfam ID: PF13925 ; PF00400
• Sequence:
  MATPVVTKTAWKLQEIVAHASNVSSLVLGKASGRLLATGGDDCRVNLWSINKPNCIMSLT
  GHTSPVESVRLNTPEELIVAGSQSGSIRVWDLEAAKILRTLMGHKANICSLDFHPYGEFV
  ASGSQDTNIKLWDIRRKGCVFRYRGHSQAVRCLRFSPDGKWLASAADDHTVKLWDLTAGK
  MMSEFPGHTGPVNVVEFHPNEYLLASGSSDRTIRFWDLEKFQVVSCIEGEPGPVRSVLFN
  PDGCCLYSGCQDSLRVYGWEPERCFDVVLVNWGKVADLAICNDQLIGVAFSQSNVSSYVV
  DLTRVTRTGTVARDPVQDHRPLAQPLPNPSAPLRRIYERPSTTCSKPQRVKQNSESERRS
  PSSEDDRDERESRAEIQNAEDYNEIFQPKNSISRTPPRRSEPFPAPPEDDAATAKEAAKP
  SPAMDVQFPVPNLEVLPRPPVVASTPAPKAEPAIIPATRNEPIGLKASDFLPAVKIPQQA
  ELVDEDAMSQIRKGHDTMCVVLTSRHKNLDTVRAVWTMGDIKTSVDSAVAINDLSVVVDL
  LNIVNQKASLWKLDLCTTVLPQIEKLLQSKYESYVQTGCTSLKLILQRFLPLITDMLAAP
  PSVGVDISREERLHKCRLCYKQLKSISGLVKSKSGLSGRHGSTFRELHLLMASLD
• Function: Participates in a complex which severs microtubules in an ATP-dependent manner. May act to target the enzymatic subunit of this complex to sites of action such as the centrosome. Microtubule severing may promote rapid reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Microtubule release from the mitotic spindle poles may allow depolymerization of the microtubule end proximal to the spindle pole, leading to poleward microtubule flux and poleward motion of chromosome. Microtubule release within the cell body of neurons may be required for their transport into neuronal processes by microtubule-dependent motor proteins. This transport is required for axonal growth.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Holoprosencephaly	DISR35EC	Definitive	Genetic Variation	[1]
Lissencephaly 6 with microcephaly	DIS4YMQP	Definitive	Autosomal recessive	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[4]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[5]
Isolated growth hormone deficiency type IA	DISLPIAM	Strong	Biomarker	[6]
Lissencephaly spectrum disorders	DISBCZL7	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[8]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[9]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Genetic Variation	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Colon cancer	DISVC52G	moderate	Biomarker	[12]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[12]
Microlissencephaly	DISUCKNT	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Katanin p80 WD40 repeat-containing subunit B1 (KATNB1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Katanin p80 WD40 repeat-containing subunit B1 (KATNB1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Katanin p80 WD40 repeat-containing subunit B1 (KATNB1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Katanin p80 WD40 repeat-containing subunit B1 (KATNB1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Katanin p80 WD40 repeat-containing subunit B1 (KATNB1).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Katanin p80 WD40 repeat-containing subunit B1 (KATNB1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Katanin p80 WD40 repeat-containing subunit B1 (KATNB1).	[16]

References

• [1] Katanin p80 regulates human cortical development by limiting centriole and cilia number.Neuron. 2014 Dec 17;84(6):1240-57. doi: 10.1016/j.neuron.2014.12.017.
• [2] Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors. Neuron. 2014 Dec 17;84(6):1226-39. doi: 10.1016/j.neuron.2014.12.014.
• [3] Panobinostat for the treatment of acute myelogenous leukemia.Expert Opin Investig Drugs. 2016 Sep;25(9):1117-31. doi: 10.1080/13543784.2016.1216971. Epub 2016 Aug 8.
• [4] Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines.J Clin Endocrinol Metab. 1997 Jun;82(6):1857-62. doi: 10.1210/jcem.82.6.4013.
• [5] Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics.Sci Rep. 2017 Jan 12;7:39902. doi: 10.1038/srep39902.
• [6] A syndrome of microcephaly, short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation.Am J Med Genet A. 2016 Mar;170(3):728-33. doi: 10.1002/ajmg.a.37484. Epub 2015 Dec 6.
• [7] LAPSER1 is a putative cytokinetic tumor suppressor that shows the same centrosome and midbody subcellular localization pattern as p80 katanin.FASEB J. 2007 Jul;21(9):2086-100. doi: 10.1096/fj.06-7254com. Epub 2007 Mar 9.
• [8] KATNB1 in the human testis and its genetic variants in fertile and oligoasthenoteratozoospermic infertile men.Andrology. 2014 Nov;2(6):884-91. doi: 10.1111/andr.276. Epub 2014 Oct 3.
• [9] Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.Mol Psychiatry. 2020 Nov;25(11):2860-2872. doi: 10.1038/s41380-019-0401-9. Epub 2019 Apr 3.
• [10] Mutant p53 (G199V) gains antiapoptotic function through signal transducer and activator of transcription 3 in anaplastic thyroid cancer cells.Mol Cancer Res. 2009 Oct;7(10):1645-54. doi: 10.1158/1541-7786.MCR-09-0117. Epub 2009 Oct 13.
• [11] Targeting cancer using KAT inhibitors to mimic lethal knockouts.Biochem Soc Trans. 2016 Aug 15;44(4):979-86. doi: 10.1042/BST20160081.
• [12] KAT3B-p300 and H3AcK18/H3AcK14 levels are prognostic markers for kidney ccRCC tumor aggressiveness and target of KAT inhibitor CPTH2.Clin Epigenetics. 2018 Apr 4;10:44. doi: 10.1186/s13148-018-0473-4. eCollection 2018.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [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] 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.
• [17] 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.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.