Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNX2V4Z)

• DOT Name: V-type proton ATPase subunit B, brain isoform (ATP6V1B2)
• Synonyms: V-ATPase subunit B 2; Endomembrane proton pump 58 kDa subunit; HO57; Vacuolar proton pump subunit B 2
• Gene Name: ATP6V1B2
• Related Disease:
  Alzheimer disease
  Autosomal dominant deafness - onychodystrophy syndrome
  Depression
  Epilepsy
  Epileptic encephalopathy, infantile or early childhood, 3
  Follicular lymphoma
  Major depressive disorder
  Spinal muscular atrophy
  DOORS syndrome
  Zimmermann-Laband syndrome
  Intellectual disability
  Osteoarthritis
• UniProt ID: VATB2_HUMAN
• PDB ID: 6WLZ; 6WM2; 6WM3; 6WM4; 7U4T; 7UNF
• Pfam ID: PF00006 ; PF02874
• Sequence:
  MALRAMRGIVNGAAPELPVPTGGPAVGAREQALAVSRNYLSQPRLTYKTVSGVNGPLVIL
  DHVKFPRYAEIVHLTLPDGTKRSGQVLEVSGSKAVVQVFEGTSGIDAKKTSCEFTGDILR
  TPVSEDMLGRVFNGSGKPIDRGPVVLAEDFLDIMGQPINPQCRIYPEEMIQTGISAIDGM
  NSIARGQKIPIFSAAGLPHNEIAAQICRQAGLVKKSKDVVDYSEENFAIVFAAMGVNMET
  ARFFKSDFEENGSMDNVCLFLNLANDPTIERIITPRLALTTAEFLAYQCEKHVLVILTDM
  SSYAEALREVSAAREEVPGRRGFPGYMYTDLATIYERAGRVEGRNGSITQIPILTMPNDD
  ITHPIPDLTGYITEGQIYVDRQLHNRQIYPPINVLPSLSRLMKSAIGEGMTRKDHADVSN
  QLYACYAIGKDVQAMKAVVGEEALTSDDLLYLEFLQKFERNFIAQGPYENRTVFETLDIG
  WQLLRIFPKEMLKRIPQSTLSEFYPRDSAKH
• Function: Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment. In renal intercalated cells, can partially compensate the lack of ATP6V1B1 and mediate secretion of protons (H+) into the urine under base-line conditions but not in conditions of acid load.
• Tissue Specificity: Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level).
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Phagosome (hsa04145)
  mTOR sig.ling pathway (hsa04150)
  Sy.ptic vesicle cycle (hsa04721)
  Collecting duct acid secretion (hsa04966)
  Vibrio cholerae infection (hsa05110)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Human papillomavirus infection (hsa05165)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Insulin receptor recycling (R-HSA-77387)
  Transferrin endocytosis and recycling (R-HSA-917977)
  Amino acids regulate mTORC1 (R-HSA-9639288)
  Ion channel transport (R-HSA-983712)
  ROS and RNS production in phagocytes (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:HS07429-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Autosomal dominant deafness - onychodystrophy syndrome	DISE5O0Q	Strong	Autosomal dominant	[2]
Depression	DIS3XJ69	Strong	Genetic Variation	[3]
Epilepsy	DISBB28L	Strong	Genetic Variation	[4]
Epileptic encephalopathy, infantile or early childhood, 3	DISIYU5W	Strong	Autosomal dominant	[5]
Follicular lymphoma	DISVEUR6	Strong	Genetic Variation	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Spinal muscular atrophy	DISTLKOB	Strong	Altered Expression	[8]
DOORS syndrome	DISMR9ZU	Supportive	Autosomal recessive	[9]
Zimmermann-Laband syndrome	DISXXVYH	Supportive	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[10]
Osteoarthritis	DIS05URM	Limited	Biomarker	[11]

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 V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[14]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[15]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[21]

1 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 affects the methylation of V-type proton ATPase subunit B, brain isoform (ATP6V1B2).	[16]

References

• [1] Human ApoE 2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on V-type H+-ATPase.J Alzheimers Dis. 2016 Jun 18;53(3):1015-31. doi: 10.3233/JAD-160307.
• [2] De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome. Cell Res. 2014 Nov;24(11):1370-3. doi: 10.1038/cr.2014.77. Epub 2014 Jun 10.
• [3] Association of ATP6V1B2 rs1106634 with lifetime risk of depression and hippocampal neurocognitive deficits: possible novel mechanisms in the etiopathology of depression.Transl Psychiatry. 2016 Nov 8;6(11):e945. doi: 10.1038/tp.2016.221.
• [4] EXOME REPORT: Novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities.Eur J Med Genet. 2020 Apr;63(4):103799. doi: 10.1016/j.ejmg.2019.103799. Epub 2019 Oct 23.
• [5] Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet. 2015 Jun;47(6):661-7. doi: 10.1038/ng.3282. Epub 2015 Apr 27.
• [6] Follicular lymphoma-associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTOR.J Clin Invest. 2019 Mar 4;129(4):1626-1640. doi: 10.1172/JCI98288. eCollection 2019 Mar 4.
• [7] Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.Mol Psychiatry. 2011 Feb;16(2):202-15. doi: 10.1038/mp.2009.125. Epub 2009 Dec 29.
• [8] Extracellular pH change modulates the exon 7 splicing in SMN2 mRNA.Mol Cell Neurosci. 2008 Oct;39(2):268-72. doi: 10.1016/j.mcn.2008.07.002. Epub 2008 Jul 11.
• [9] DOORS syndrome and a recurrent?truncating ATP6V1B2 variant. Genet Med. 2021 Jan;23(1):149-154. doi: 10.1038/s41436-020-00950-9. Epub 2020 Sep 2.
• [10] A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability.EBioMedicine. 2019 Jul;45:408-421. doi: 10.1016/j.ebiom.2019.06.035. Epub 2019 Jun 27.
• [11] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [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] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.