Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMLXQZ4)

• DOT Name: Cytosolic carboxypeptidase-like protein 5 (AGBL5)
• Synonyms: EC 3.4.17.-; EC 3.4.17.24; ATP/GTP-binding protein-like 5; Protein deglutamylase CCP5
• Gene Name: AGBL5
• Related Disease:
  Male infertility
  Retinitis pigmentosa 75
  Retinopathy
  Retinitis pigmentosa
• UniProt ID: CBPC5_HUMAN
• EC Number: 3.4.17.-; 3.4.17.24
• Pfam ID: PF18027 ; PF00246
• Sequence:
  MELRCGGLLFSSRFDSGNLAHVEKVESLSSDGEGVGGGASALTSGIASSPDYEFNVWTRP
  DCAETEFENGNRSWFYFSVRGGMPGKLIKINIMNMNKQSKLYSQGMAPFVRTLPTRPRWE
  RIRDRPTFEMTETQFVLSFVHRFVEGRGATTFFAFCYPFSYSDCQELLNQLDQRFPENHP
  THSSPLDTIYYHRELLCYSLDGLRVDLLTITSCHGLREDREPRLEQLFPDTSTPRPFRFA
  GKRIFFLSSRVHPGETPSSFVFNGFLDFILRPDDPRAQTLRRLFVFKLIPMLNPDGVVRG
  HYRTDSRGVNLNRQYLKPDAVLHPAIYGAKAVLLYHHVHSRLNSQSSSEHQPSSCLPPDA
  PVSDLEKANNLQNEAQCGHSADRHNAEAWKQTEPAEQKLNSVWIMPQQSAGLEESAPDTI
  PPKESGVAYYVDLHGHASKRGCFMYGNSFSDESTQVENMLYPKLISLNSAHFDFQGCNFS
  EKNMYARDRRDGQSKEGSGRVAIYKASGIIHSYTLECNYNTGRSVNSIPAACHDNGRASP
  PPPPAFPSRYTVELFEQVGRAMAIAALDMAECNPWPRIVLSEHSSLTNLRAWMLKHVRNS
  RGLSSTLNVGVNKKRGLRTPPKSHNGLPVSCSENTLSRARSFSTGTSAGGSSSSQQNSPQ
  MKNSPSFPFHGSRPAGLPGLGSSTQKVTHRVLGPVREPRSQDRRRQQQPLNHRPAGSLAP
  SPAPTSSGPASSHKLGSCLLPDSFNIPGSSCSLLSSGDKPEAVMVIGKGLLGTGARMPCI
  KTRLQARPRLGRGSPPTRRGMKGSSGPTSPTPRTRESSELELGSCSATPGLPQARPPRPR
  SAPAFSPISCSLSDSPSWNCYSRGPLGQPEVCFVPKSPPLTVSPRV
• 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 alpha- and beta-tubulin. Cleaves alpha- and gamma-linked polyglutamate tubulin side-chain, as well as the branching point glutamate. Also catalyzes the removal of alpha-linked glutamate residues from the carboxy-terminus of alpha-tubulin. Mediates deglutamylation of nucleotidyltransferase CGAS, leading to CGAS antiviral defense response activation.
• Tissue Specificity: Expressed in brain.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Male infertility	DISY3YZZ	Strong	Biomarker	[1]
Retinitis pigmentosa 75	DISVQWJO	Strong	Genetic Variation	[2]
Retinopathy	DISB4B0F	moderate	Biomarker	[3]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[4]

10 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-like protein 5 (AGBL5).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytosolic carboxypeptidase-like protein 5 (AGBL5).	[14]

References

• [1] Loss of the deglutamylase CCP5 perturbs multiple steps of spermatogenesis and leads to male infertility.J Cell Sci. 2019 Feb 7;132(3):jcs226951. doi: 10.1242/jcs.226951.
• [2] Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies.Genet Med. 2016 Jun;18(6):554-62. doi: 10.1038/gim.2015.127. Epub 2015 Sep 10.
• [3] Pathological but not physiological retinal neovascularization is altered in TNF-Rp55-receptor-deficient mice.Invest Ophthalmol Vis Sci. 2006 Nov;47(11):5057-65. doi: 10.1167/iovs.06-0407.
• [4] Exome Sequencing Reveals AGBL5 as Novel Candidate Gene and Additional Variants for Retinitis Pigmentosa in Five Turkish Families. Invest Ophthalmol Vis Sci. 2015 Dec;56(13):8045-53. doi: 10.1167/iovs.15-17473.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] 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.