Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR92JFR)

• DOT Name: Cytosolic carboxypeptidase 1 (AGTPBP1)
• Synonyms: EC 3.4.17.-; EC 3.4.17.24; ATP/GTP-binding protein 1; Nervous system nuclear protein induced by axotomy protein 1 homolog; Protein deglutamylase CCP1
• Gene Name: AGTPBP1
• Related Disease:
  Neurodegeneration, childhood-onset, with cerebellar atrophy
  Cerebellar ataxia
  Cerebellar degeneration
  Male infertility
  Measles
  Motor neurone disease
  Peripheral neuropathy
  Pontocerebellar hypoplasia type 1A
  Neuroblastoma
  Neurodegenerative disease
  Pontocerebellar hypoplasia type 1
  Cognitive impairment
• UniProt ID: CBPC1_HUMAN
• EC Number: 3.4.17.-; 3.4.17.24
• Pfam ID: PF18027 ; PF00246
• Sequence:
  MSKLKVIPEKSLTNNSRIVGLLAQLEKINAEPSESDTARYVTSKILHLAQSQEKTRREMT
  AKGSTGMEILLSTLENTKDLQTTLNILSILVELVSAGGGRRVSFLVTKGGSQILLQLLMN
  ASKESPPHEDLMVQIHSILAKIGPKDKKFGVKARINGALNITLNLVKQNLQNHRLVLPCL
  QLLRVYSANSVNSVSLGKNGVVELMFKIIGPFSKKNSSLIKVALDTLAALLKSKTNARRA
  VDRGYVQVLLTIYVDWHRHDNRHRNMLIRKGILQSLKSVTNIKLGRKAFIDANGMKILYN
  TSQECLAVRTLDPLVNTSSLIMRKCFPKNRLPLPTIKSSFHFQLPVIPVTGPVAQLYSLP
  PEVDDVVDESDDNDDIDVEAENETENEDDLDQNFKNDDIETDINKLKPQQEPGRTIEDLK
  MYEHLFPELVDDFQDYDLISKEPKPFVFEGKVRGPIVVPTAGEETSGNSGNLRKVVMKEN
  ISSKGDEGEKKSTFMDLAKEDIKDNDRTLQQQPGDQNRTISSVHGLNNDIVKALDRITLQ
  NIPSQTAPGFTAEMKKDCSLPLTVLTCAKACPHMATCGNVLFEGRTVQLGKLCCTGVETE
  DDEDTESNSSVEQASVEVPDGPTLHDPDLYIEIVKNTKSVPEYSEVAYPDYFGHIPPPFK
  EPILERPYGVQRTKIAQDIERLIHQSDIIDRVVYDLDNPNYTIPEEGDILKFNSKFESGN
  LRKVIQIRKNEYDLILNSDINSNHYHQWFYFEVSGMRPGVAYRFNIINCEKSNSQFNYGM
  QPLMYSVQEALNARPWWIRMGTDICYYKNHFSRSSVAAGGQKGKSYYTITFTVNFPHKDD
  VCYFAYHYPYTYSTLQMHLQKLESAHNPQQIYFRKDVLCETLSGNSCPLVTITAMPESNY
  YEHICHFRNRPYVFLSARVHPGETNASWVMKGTLEYLMSNNPTAQSLRESYIFKIVPMLN
  PDGVINGNHRCSLSGEDLNRQWQSPSPDLHPTIYHAKGLLQYLAAVKRLPLVYCDYHGHS
  RKKNVFMYGCSIKETVWHTNDNATSCDVVEDTGYRTLPKILSHIAPAFCMSSCSFVVEKS
  KESTARVVVWREIGVQRSYTMESTLCGCDQGKYKGLQIGTRELEEMGAKFCVGLLRLKRL
  TSPLEYNLPSSLLDFENDLIESSCKVTSPTTYVLDEDEPRFLEEVDYSAESNDELDIELA
  ENVGDYEPSAQEEVLSDSELSRTYLP
• Function: Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins. Catalyzes the removal of polyglutamate side chains present on the gamma-carboxyl group of glutamate residues within the C-terminal tail of alpha- and beta-tubulin. Specifically cleaves tubulin long-side-chains, while it is not able to remove the branching point glutamate. Also catalyzes the removal of polyglutamate residues from the carboxy-terminus of alpha-tubulin as well as non-tubulin proteins such as MYLK. Involved in KLF4 deglutamylation which promotes KLF4 proteasome-mediated degradation, thereby negatively regulating cell pluripotency maintenance and embryogenesis.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration, childhood-onset, with cerebellar atrophy	DISDXGE1	Definitive	Autosomal recessive	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[2]
Cerebellar degeneration	DISPBCM3	Strong	Genetic Variation	[2]
Male infertility	DISY3YZZ	Strong	Biomarker	[3]
Measles	DISXSUID	Strong	Biomarker	[4]
Motor neurone disease	DISUHWUI	Strong	Biomarker	[2]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[2]
Pontocerebellar hypoplasia type 1A	DIS7X0VS	Strong	Biomarker	[2]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[5]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[6]
Pontocerebellar hypoplasia type 1	DISU1PSQ	Supportive	Autosomal recessive	[2]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[7]

11 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 Cytosolic carboxypeptidase 1 (AGTPBP1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytosolic carboxypeptidase 1 (AGTPBP1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytosolic carboxypeptidase 1 (AGTPBP1).	[14]

References

• [1] Biallelic variant in AGTPBP1 causes infantile lower motor neuron degeneration and cerebellar atrophy. Am J Med Genet A. 2019 Aug;179(8):1580-1584. doi: 10.1002/ajmg.a.61198. Epub 2019 May 18.
• [2] Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy. Eur J Hum Genet. 2019 Sep;27(9):1419-1426. doi: 10.1038/s41431-019-0400-y. Epub 2019 Apr 11.
• [3] Role of Cytosolic Carboxypeptidase 5 in Neuronal Survival and Spermatogenesis.Sci Rep. 2017 Jan 27;7:41428. doi: 10.1038/srep41428.
• [4] Cutting edge: inhibiting measles virus infection but promoting reproduction: an explanation for splicing and tissue-specific expression of CD46.J Immunol. 2002 Nov 15;169(10):5405-9. doi: 10.4049/jimmunol.169.10.5405.
• [5] Regulation of cell proliferation and apoptosis in neuroblastoma cells by ccp1, a FGF2 downstream gene.BMC Cancer. 2010 Nov 30;10:657. doi: 10.1186/1471-2407-10-657.
• [6] The carboxypeptidase-like substrate-binding site in Nna1 is essential for the rescue of the Purkinje cell degeneration (pcd) phenotype.Mol Cell Neurosci. 2006 Oct;33(2):200-13. doi: 10.1016/j.mcn.2006.07.009. Epub 2006 Sep 6.
• [7] The effects of cerebellar damage on maze learning in animals.Cerebellum. 2003;2(4):300-9. doi: 10.1080/14734220310017456.
• [8] 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.
• [9] 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.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.