Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOX2H61)

• DOT Name: Cytosolic carboxypeptidase 6 (AGBL4)
• Synonyms: EC 3.4.17.24; ATP/GTP-binding protein-like 4; Protein deglutamylase CCP6
• Gene Name: AGBL4
• Related Disease:
  Age-related macular degeneration
  Alcohol dependence
  Atrial fibrillation
  Drug dependence
  Major depressive disorder
  Schizophrenia
  Substance abuse
  Substance dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Endometriosis
  Familial atrial fibrillation
  Heroin dependence
  Neoplasm of esophagus
• UniProt ID: CBPC6_HUMAN
• EC Number: 3.4.17.24
• Pfam ID: PF18027 ; PF00246
• Sequence:
  MAEGSQSAPEAGNDMGNDDAIGGNVSKYIVLPTGYCGQPKKGHLIFDACFESGNLGRVDQ
  VSEFEYDLFIRPDTCNPRFRVWFNFTVENVKESQRVIFNIVNFSKTKSLYRDGMAPMVKS
  TSRPKWQRLPPKNVYYYRCPDHRKNYVMSFAFCFDREEDIYQFAYCYPYTYTRFQHYLDS
  LQKRNMDYFFREQLGQSVQQRKLDLLTITSPDNLREGAEQKVVFITGRVHPGETPSSFVC
  QGIIDFLVSQHPIACVLREYLVFKIAPMLNPDGVYLGNYRCSLMGFDLNRHWLDPSPWVH
  PTLHGVKQLIVQMYNDPKTSLEFYIDIHAHSTMMNGFMYGNIFEDEERFQRQAIFPKLLC
  QNAEDFSYSSTSFNRDAVKAGTGRRFLGGLLDHTSYCYTLEVSFYSYIISGTTAAVPYTE
  EAYMKLGRNVARTFLDYYRLNPVVEKVAIPMPRLRNKEIEVQRRKEKSPPYKHPLLRGPA
  SNYPNSKGDKKSSVNHKDPSTPF
• 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 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. Mediates the deglutamylation of nucleotidyltransferase CGAS, leading to CGAS antiviral defense response activation. 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[2]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[3]
Drug dependence	DIS9IXRC	Strong	Biomarker	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Substance abuse	DIS327VW	Strong	Biomarker	[4]
Substance dependence	DISDRAAR	Strong	Biomarker	[4]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[2]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[2]
Endometriosis	DISX1AG8	moderate	Genetic Variation	[6]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[3]
Heroin dependence	DISQ1H57	moderate	Genetic Variation	[2]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[7]

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 6 (AGBL4).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Cytosolic carboxypeptidase 6 (AGBL4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytosolic carboxypeptidase 6 (AGBL4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cytosolic carboxypeptidase 6 (AGBL4).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Cytosolic carboxypeptidase 6 (AGBL4).	[12]

References

• [1] Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions.J Immunol. 2013 Mar 1;190(5):2049-57. doi: 10.4049/jimmunol.1201751. Epub 2013 Jan 30.
• [2] Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence.Mol Psychiatry. 2021 Apr;26(4):1152-1161. doi: 10.1038/s41380-019-0497-y. Epub 2019 Aug 28.
• [3] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [4] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [5] Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression.Mol Psychiatry. 2020 Jul;25(7):1420-1429. doi: 10.1038/s41380-018-0336-6. Epub 2019 Jan 9.
• [6] New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population-The genome-wide association study.Eur J Obstet Gynecol Reprod Biol. 2017 Oct;217:106-112. doi: 10.1016/j.ejogrb.2017.08.037. Epub 2017 Sep 1.
• [7] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] 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.
• [11] 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.
• [12] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.