Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8NQLH0)

• DOT Name: Cytosolic carboxypeptidase 4 (AGBL1)
• Synonyms: EC 3.4.17.-; EC 3.4.17.24; ATP/GTP-binding protein-like 1; Protein deglutamylase CCP4
• Gene Name: AGBL1
• Related Disease:
  Alzheimer disease
  Autism
  Fleck corneal dystrophy
  Narcolepsy
  Bronchopulmonary dysplasia
  Fuchs' endothelial dystrophy
• UniProt ID: CBPC4_HUMAN
• EC Number: 3.4.17.-; 3.4.17.24
• Pfam ID: PF18027 ; PF00246
• Sequence:
  MAEQEASGLQVLLHTLQSSSDKESILTILKVLGDLLSVGTDRRIHYMISKGGSEALLQTL
  VDTARTAPPDYDILLPLFRLLAKVGLRDKKIGRKALELEALDVTLILARKNLSHGQNLLH
  CLWALRVFASSVSMGAMLGINGAMELLFKVITPYTRKRTQAIRAATEVLAALLKSKSNGR
  RAVNRGYVTSLLGLHQDWHSHDTANAYVQIRRGLLLCLRHIAALRSGREAFLAAQGMEIL
  FSTTQNCLDDKSMEPVISVVLQILRQCYPTSPLPLVTASSAYAFPVPGCITTEPPHDLPE
  EDFEDDGDDEVDKDSDTEDGKVEDDDLETDVNKLSSKPGLDRPEEELMQYEVMCLELSYS
  FEELQSKLGDDLNSEKTQYANHHHIPAAASSKQHCYSKDQSSCGQEREYAVQTSLLCRVK
  TGRSTVHLGSKKNPGVNLYQNVQSNSLRRDSSESEIPDIQASPKADAWDVDAIFCPRMSA
  SFSNSTRTREVVKVIDKLLQTHLKRVPFHDPYLYMAKARRTSSVVDFKMMAFPDVWGHCP
  PPTTQPMLERKCGVQRIRIFEDIRRLIQPSDVINKVVFSLDEPWPLQDNASNCLRFFSKF
  ESGNLRKAIQVREFEYDLLVNADVNSTQHQQWFYFKVSGMQAAIPYHFNIINCEKPNSQF
  NYGMQPTLYSVKEALLGKPTWIRTGHEICYYKNHYRQSTAVAGGASGKCYYTLTFAVTFP
  HSEDVCYLAYHYPYTYTALMTHLDILEKSVNLKEVYFRQDVLCQTLGGNPCPLVTITAMP
  ESNSDEHLEQFRHRPYQVITARVHPGESNASWVMKGTLEFLVSSDPVARLLRENFIFKII
  PMLNPDGVINGNHRCSLSGEDLNRQWLSPSAHLQPTIYHAKGLLYHLSSIGRSPVVFCDF
  HGHSQKKNVFLYGCSIKETLWQAACTVGTSTILEEVNYRTLPKILDKLAPAFTMSSCSFL
  VEKSRASTARVVVWREMGVSRSYTMESSYCGCNQGPYQCTQRLLERTKNERAHPVDGLQG
  LQFGTRELEEMGAMFCLGLLILELKSASCSHQLLAQAATLLSAEEDALDQHLQRLKSSNF
  LPKHIWFAYHFFAITNFFKMNLLLHVSPVCDT
• Function: Metallocarboxypeptidase that mediates 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 tubulin protein. 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 non-tubulin proteins such as MYLK.
• Tissue Specificity: Expressed in corneal endothelium.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Fleck corneal dystrophy	DISERQJ1	Strong	Biomarker	[3]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[4]
Bronchopulmonary dysplasia	DISO0BY5	moderate	Genetic Variation	[5]
Fuchs' endothelial dystrophy	DISL7TXC	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Cytosolic carboxypeptidase 4 (AGBL1) increases the Schizophrenia ADR of Methamphetamine.	[11]
Chlorothiazide	DMLHESP	Approved	Cytosolic carboxypeptidase 4 (AGBL1) increases the Metabolic disorder ADR of Chlorothiazide.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cytosolic carboxypeptidase 4 (AGBL1).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Cytosolic carboxypeptidase 4 (AGBL1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cytosolic carboxypeptidase 4 (AGBL1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cytosolic carboxypeptidase 4 (AGBL1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cytosolic carboxypeptidase 4 (AGBL1).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cytosolic carboxypeptidase 4 (AGBL1).	[10]

References

• [1] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [2] Genome-wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders.Autism Res. 2020 Mar;13(3):382-396. doi: 10.1002/aur.2229. Epub 2019 Oct 24.
• [3] Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4. Am J Hum Genet. 2013 Oct 3;93(4):758-64. doi: 10.1016/j.ajhg.2013.08.010.
• [4] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [5] Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2011 Nov 15;184(10):1164-70. doi: 10.1164/rccm.201103-0548OC. Epub 2011 Aug 11.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] 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.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [11] Evidence for shared genetic risk between methamphetamine-induced psychosis and schizophrenia. Neuropsychopharmacology. 2013 Sep;38(10):1864-70. doi: 10.1038/npp.2013.94. Epub 2013 Apr 12.
• [12] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.