Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCX9987)

• DOT Name: Cytosolic carboxypeptidase 2 (AGBL2)
• Synonyms: EC 3.4.17.-; ATP/GTP-binding protein-like 2; Protein deglutamylase CCP2
• Gene Name: AGBL2
• Related Disease:
  OPTN-related open angle glaucoma
  Primary biliary cholangitis
  Primary sclerosing cholangitis
  Tuberculosis
  Advanced cancer
  Anxiety
  Cardiac arrest
  Cardiovascular disease
  Epithelial ovarian cancer
  Herpes simplex infection
  Measles
  Medullary thyroid gland carcinoma
  Multiple sclerosis
  Myocardial infarction
  Neoplasm
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Skin and skin-structure infection
  Stroke
  Breast cancer
  Breast carcinoma
  Epilepsy
  Epstein barr virus infection
  Hepatocellular carcinoma
  IgA nephropathy
• UniProt ID: CBPC2_HUMAN
• EC Number: 3.4.17.-
• Pfam ID: PF18027 ; PF00246
• Sequence:
  MFPALETHLKQTIPDPYEDFMYRHLQYYGYFKAQRGSLPNSATHQHVRKNNPQCLLNGSL
  GEKDDLIPDTLQKEKLLWPISLSSAVHRQIEAINRDFHSCLGWMQWRGLSSLQPPPPRFK
  DSPASAFRVAGITDSHMLSLPHLRSRQLLYDELDEVNPRLREPQELFSILSTKRPLQAPR
  WPIECEVIKENIHHIEWAPPQPEYFYQPKGNEKVPEIVGEKKGTVVYQLDSVPIEGSYFT
  SSRVGGKRGIVKELAVTLQGPEDNTLLFESRFESGNLQKAVRVDTYEYELTLRTDLYTNK
  HTQWFYFRVQNTRKDATYRFTIVNLLKPKSLYTVGMKPLLYSQLDANTRNIGWRREGNEI
  KYYKNNTDDGQQPFYCLTWTIQFPYDQDTCFFAHFYPYTYTDLQCYLLSVANNPIQSQFC
  KLQTLCRSLAGNTVYLLTITNPSQTPQEAAAKKAVVLSARVHPGESNGSWVMKGFLDFIL
  SNSPDAQLLRDIFVFKVLPMLNPDGVIVGNYRCSLAGRDLNRHYKTILKESFPCIWYTRN
  MIKRLLEEREVLLYCDFHGHSRKNNIFLYGCNNNNRKYWLHERVFPLMLCKNAPDKFSFH
  SCNFKVQKCKEGTGRVVMWRMGILNSYTMESTFGGSTLGNKRDTHFTIEDLKSLGYHVCD
  TLLDFCDPDQMKFTQCLAELKELLRQEIHKKFHELGQDVDLEGSWSDISLSDIESSTSGS
  DSSLSDGLPVHLANIADELTQKKKMFKKKKKKSLQTRKQRNEQYQKKNLMQKLKLTEDTS
  EKAGFASTLQKQPTFFKNSENSSFLPMKNENPRLNETNLNRRDKDTPLDPSMATLILPKN
  KGRMQNKKPGFTVSCSPKRTINSSQEPAPGMKPNWPRSRYPATKRGCAAMAAYPSLHIYT
  YP
• 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.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Biomarker	[2]
Primary sclerosing cholangitis	DISTH5WJ	Definitive	Biomarker	[2]
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Anxiety	DISIJDBA	Strong	Genetic Variation	[5]
Cardiac arrest	DIS9DIA4	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[8]
Measles	DISXSUID	Strong	Biomarker	[9]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[10]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[11]
Myocardial infarction	DIS655KI	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Osteoporosis	DISF2JE0	Strong	Biomarker	[12]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[7]
Skin and skin-structure infection	DIS3F9EY	Strong	Biomarker	[13]
Stroke	DISX6UHX	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[14]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[14]
Epilepsy	DISBB28L	Limited	Autosomal recessive	[15]
Epstein barr virus infection	DISOO0WT	Limited	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[17]
IgA nephropathy	DISZ8MTK	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[22]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cytosolic carboxypeptidase 2 (AGBL2).	[27]

2 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 decreases the methylation of Cytosolic carboxypeptidase 2 (AGBL2).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cytosolic carboxypeptidase 2 (AGBL2).	[26]

References

• [1] Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.PLoS One. 2017 Aug 23;12(8):e0183709. doi: 10.1371/journal.pone.0183709. eCollection 2017.
• [2] Prevalence of autoimmune diseases and clinical significance of autoantibody profile: Data from National Institute of Hygiene in Rabat, Morocco.Hum Immunol. 2019 Jul;80(7):523-532. doi: 10.1016/j.humimm.2019.02.012. Epub 2019 Feb 23.
• [3] Construction of human MASP-2-CCP1/2SP, CCP2SP, SP plasmid DNA nanolipoplexes and the effects on tuberculosis in BCG-infected mice.Microb Pathog. 2017 Aug;109:200-208. doi: 10.1016/j.micpath.2017.05.043. Epub 2017 May 31.
• [4] Tumor suppressor RARRES1 links tubulin deglutamylation to mitochondrial metabolism and cell survival.Oncotarget. 2019 Feb 26;10(17):1606-1624. doi: 10.18632/oncotarget.26600. eCollection 2019 Feb 26.
• [5] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [6] Association of Rheumatoid Factors With Subclinical and Clinical Atherosclerosis in African American Women: The Multiethnic Study of Atherosclerosis.Arthritis Care Res (Hoboken). 2017 Feb;69(2):166-174. doi: 10.1002/acr.22930.
• [7] High expression of AGBL2 is a novel prognostic factor of adverse outcome in patients with ovarian carcinoma.Oncol Lett. 2019 Nov;18(5):4900-4906. doi: 10.3892/ol.2019.10829. Epub 2019 Sep 9.
• [8] Associations between Viral Infection History Symptoms, Granulocyte Reactive Oxygen Species Activity, and Active Rheumatoid Arthritis Disease in Untreated Women at Onset: Results from a Longitudinal Cohort Study of Tatarstan Women.Front Immunol. 2017 Dec 5;8:1725. doi: 10.3389/fimmu.2017.01725. eCollection 2017.
• [9] 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.
• [10] Specific immunostaining for CCP II, a novel calcitonin carboxyl terminal peptide encoded by the calcitonin/CGRP gene.J Histochem Cytochem. 1993 Nov;41(11):1605-10. doi: 10.1177/41.11.7691931.
• [11] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [12] Association of Low Bone Mineral Density with Anti-Citrullinated Protein Antibody Positivity and Disease Activity in Established Rheumatoid Arthritis: Findings from a US Observational Cohort.Adv Ther. 2018 Feb;35(2):232-242. doi: 10.1007/s12325-017-0657-x. Epub 2018 Jan 25.
• [13] Prevalence and Incidence of Upper Respiratory Tract Infection Events Are Elevated Prior to the Development of Rheumatoid Arthritis in First-Degree Relatives.Front Immunol. 2018 Nov 29;9:2771. doi: 10.3389/fimmu.2018.02771. eCollection 2018.
• [14] Clinical implications of AGBL2 expression and its inhibitor latexin in breast cancer.World J Surg Oncol. 2014 May 7;12:142. doi: 10.1186/1477-7819-12-142.
• [15] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [16] Anti-citrullinated protein antibody response after primary EBV infection in kidney transplant patients.PLoS One. 2018 May 10;13(5):e0197219. doi: 10.1371/journal.pone.0197219. eCollection 2018.
• [17] AGBL2 promotes cancer cell growth through IRGM-regulated autophagy and enhanced Aurora A activity in hepatocellular carcinoma.Cancer Lett. 2018 Feb 1;414:71-80. doi: 10.1016/j.canlet.2017.11.003. Epub 2017 Nov 8.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] 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.
• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [23] 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.
• [24] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [25] 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.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] 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.