Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1I0IBK)

• DOT Name: Mitochondrial disaggregase (CLPB)
• Synonyms: EC 3.6.1.-; Suppressor of potassium transport defect 3
• Gene Name: CLPB
• Related Disease:
  3-methylglutaconic aciduria, type VIIB
  3-methylglutaconic aciduria
  Acute myelogenous leukaemia
  Cataract
  Chronic granulomatous disease
  Intellectual disability
  Nephrocalcinosis
  Neutropenia, severe congenital, 9, autosomal dominant
  Severe congenital neutropenia
  Leigh syndrome
  Neuroblastoma
• UniProt ID: CLPB_HUMAN
• PDB ID: 7TTR; 7TTS; 7US2; 7XBK; 7XC5; 8DEH; 8FDS
• EC Number: 3.6.1.-
• Pfam ID: PF07724 ; PF12796 ; PF10431
• Sequence:
  MLGSLVLRRKALAPRLLLRLLRSPTLRGHGGASGRNVTTGSLGEPQWLRVATGGRPGTSP
  ALFSGRGAATGGRQGGRFDTKCLAAATWGRLPGPEETLPGQDSWNGVPSRAGLGMCALAA
  ALVVHCYSKSPSNKDAALLEAARANNMQEVSRLLSEGADVNAKHRLGWTALMVAAINRNN
  SVVQVLLAAGADPNLGDDFSSVYKTAKEQGIHSLEDGGQDGASRHITNQWTSALEFRRWL
  GLPAGVLITREDDFNNRLNNRASFKGCTALHYAVLADDYRTVKELLDGGANPLQRNEMGH
  TPLDYAREGEVMKLLRTSEAKYQEKQRKREAEERRRFPLEQRLKEHIIGQESAIATVGAA
  IRRKENGWYDEEHPLVFLFLGSSGIGKTELAKQTAKYMHKDAKKGFIRLDMSEFQERHEV
  AKFIGSPPGYVGHEEGGQLTKKLKQCPNAVVLFDEVDKAHPDVLTIMLQLFDEGRLTDGK
  GKTIDCKDAIFIMTSNVASDEIAQHALQLRQEALEMSRNRIAENLGDVQISDKITISKNF
  KENVIRPILKAHFRRDEFLGRINEIVYFLPFCHSELIQLVNKELNFWAKRAKQRHNITLL
  WDREVADVLVDGYNVHYGARSIKHEVERRVVNQLAAAYEQDLLPGGCTLRITVEDSDKQL
  LKSPELPSPQAEKRLPKLRLEIIDKDSKTRRLDIRAPLHPEKVCNTI
• Function: Functions as a regulatory ATPase and participates in secretion/protein trafficking process. Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins. Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6. Plays a role in granulocyte differentiation.
• Tissue Specificity: Widely expressed (at protein level) . Expressed in fetal, as well as in adult tissues, with highest levels in adult brain, including thalamus, hippocampus, occipital cortex and parietal cortex. Low expression in granulocytes .
• KEGG Pathway: Longevity regulating pathway - multiple species (hsa04213)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylglutaconic aciduria, type VIIB	DISQIS1L	Definitive	Autosomal recessive	[1]
3-methylglutaconic aciduria	DIS8G1WP	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Cataract	DISUD7SL	Strong	Biomarker	[1]
Chronic granulomatous disease	DIS9ZR24	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Nephrocalcinosis	DIS5ZVJP	Strong	Biomarker	[6]
Neutropenia, severe congenital, 9, autosomal dominant	DISSL827	Strong	Autosomal dominant	[7]
Severe congenital neutropenia	DISES99N	Strong	Biomarker	[5]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[8]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[9]

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 Mitochondrial disaggregase (CLPB).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial disaggregase (CLPB).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial disaggregase (CLPB).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mitochondrial disaggregase (CLPB).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial disaggregase (CLPB).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Mitochondrial disaggregase (CLPB).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitochondrial disaggregase (CLPB).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitochondrial disaggregase (CLPB).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitochondrial disaggregase (CLPB).	[18]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Mitochondrial disaggregase (CLPB).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitochondrial disaggregase (CLPB).	[19]

References

• [1] A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients. J Inherit Metab Dis. 2017 Nov;40(6):853-860. doi: 10.1007/s10545-017-0057-z. Epub 2017 Jul 7.
• [2] Mitochondrial dysfunction, AMPK activation and peroxisomal metabolism: A coherent scenario for non-canonical 3-methylglutaconic acidurias.Biochimie. 2020 Jan;168:53-82. doi: 10.1016/j.biochi.2019.10.004. Epub 2019 Oct 15.
• [3] Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment.Cancer Discov. 2019 Jul;9(7):890-909. doi: 10.1158/2159-8290.CD-19-0117. Epub 2019 May 2.
• [4] Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease.Infect Immun. 2015 Nov;83(11):4277-92. doi: 10.1128/IAI.00778-15. Epub 2015 Aug 17.
• [5] CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.Am J Hum Genet. 2015 Feb 5;96(2):245-57. doi: 10.1016/j.ajhg.2014.12.013. Epub 2015 Jan 15.
• [6] Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.J Inherit Metab Dis. 2015 Mar;38(2):211-9. doi: 10.1007/s10545-015-9813-0. Epub 2015 Jan 18.
• [7] Heterozygous variants of CLPB are a cause of severe congenital neutropenia. Blood. 2022 Feb 3;139(5):779-791. doi: 10.1182/blood.2021010762.
• [8] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [9] Recombinant heat shock protein 78 enhances enterovirus 71 propagation in Vero cells and is induced in SK-N-SH cells during the infection.Arch Virol. 2017 Jun;162(6):1649-1660. doi: 10.1007/s00705-017-3287-3. Epub 2017 Feb 24.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] 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.
• [18] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [19] 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.