Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8FQ7MN)

• DOT Name: V-type proton ATPase subunit B, kidney isoform (ATP6V1B1)
• Synonyms: V-ATPase subunit B 1; Endomembrane proton pump 58 kDa subunit; Vacuolar proton pump subunit B 1
• Gene Name: ATP6V1B1
• Related Disease:
  Infantile malignant osteopetrosis
  Renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss
  Deafness
  Distal renal tubular acidosis
  Medullary sponge kidney
  Nephrocalcinosis
  Osteopetrosis
  Hearing loss, autosomal recessive
  Autosomal recessive distal renal tubular acidosis
  Renal tubular acidosis
• UniProt ID: VATB1_HUMAN
• Pfam ID: PF00006 ; PF02874
• Sequence:
  MAMEIDSRPGGLPGSSCNLGAAREHMQAVTRNYITHPRVTYRTVCSVNGPLVVLDRVKFA
  QYAEIVHFTLPDGTQRSGQVLEVAGTKAIVQVFEGTSGIDARKTTCEFTGDILRTPVSED
  MLGRVFNGSGKPIDKGPVVMAEDFLDINGQPINPHSRIYPEEMIQTGISPIDVMNSIARG
  QKIPIFSAAGLPHNEIAAQICRQAGLVKKSKAVLDYHDDNFAIVFAAMGVNMETARFFKS
  DFEQNGTMGNVCLFLNLANDPTIERIITPRLALTTAEFLAYQCEKHVLVILTDMSSYAEA
  LREVSAAREEVPGRRGFPGYMYTDLATIYERAGRVEGRGGSITQIPILTMPNDDITHPIP
  DLTGFITEGQIYVDRQLHNRQIYPPINVLPSLSRLMKSAIGEGMTRKDHGDVSNQLYACY
  AIGKDVQAMKAVVGEEALTSEDLLYLEFLQKFEKNFINQGPYENRSVFESLDLGWKLLRI
  FPKEMLKRIPQAVIDEFYSREGALQDLAPDTAL
• 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. Essential for the proper assembly and activity of V-ATPase. In renal intercalated cells, mediates secretion of protons (H+) into the urine thereby ensuring correct urinary acidification. Required for optimal olfactory function by mediating the acidification of the nasal olfactory epithelium.
• Tissue Specificity: Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level) . Expressed in the cochlea and endolymphatic sac .
• 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:HS03975-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile malignant osteopetrosis	DIS8C3LZ	Definitive	Genetic Variation	[1]
Renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss	DISICJDV	Definitive	Autosomal recessive	[2]
Deafness	DISKCLH4	Strong	Biomarker	[3]
Distal renal tubular acidosis	DISP6CYE	Strong	Genetic Variation	[4]
Medullary sponge kidney	DISA0949	Strong	Genetic Variation	[5]
Nephrocalcinosis	DIS5ZVJP	Strong	Genetic Variation	[6]
Osteopetrosis	DIS7GHNM	Strong	Genetic Variation	[7]
Hearing loss, autosomal recessive	DIS8G9R9	moderate	Biomarker	[8]
Autosomal recessive distal renal tubular acidosis	DISCJR4O	Supportive	Autosomal recessive	[9]
Renal tubular acidosis	DISE1NDR	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[15]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[16]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of V-type proton ATPase subunit B, kidney isoform (ATP6V1B1).	[18]

References

• [1] New insights into the pathogenesis of renal tubular acidosis--from functional to molecular studies.Pediatr Nephrol. 2000 Oct;14(12):1121-36. doi: 10.1007/s004670000407.
• [2] 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.
• [3] Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet. 1999 Jan;21(1):84-90. doi: 10.1038/5022.
• [4] ATP6V1B1 recurrent mutations in Algerian deaf patients associated with renal tubular acidosis.Int J Pediatr Otorhinolaryngol. 2020 Feb;129:109772. doi: 10.1016/j.ijporl.2019.109772. Epub 2019 Nov 9.
• [5] Medullary sponge kidney associated with primary distal renal tubular acidosis and mutations of the H+-ATPase genes.Nephrol Dial Transplant. 2009 Sep;24(9):2734-8. doi: 10.1093/ndt/gfp160. Epub 2009 Apr 13.
• [6] Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis.J Nephrol. 2018 Aug;31(4):511-522. doi: 10.1007/s40620-017-0447-1. Epub 2017 Oct 9.
• [7] A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. J Med Genet. 2003 Feb;40(2):115-21. doi: 10.1136/jmg.40.2.115.
• [8] Hearing loss without overt metabolic acidosis in ATP6V1B1 deficient MRL mice, a new genetic model for non-syndromic deafness with enlarged vestibular aqueducts.Hum Mol Genet. 2017 Oct 1;26(19):3722-3735. doi: 10.1093/hmg/ddx257.
• [9] Mutational analyses of the ATP6V1B1 and ATP6V0A4 genes in patients with primary distal renal tubular acidosis. Nephrol Dial Transplant. 2013 Aug;28(8):2123-30. doi: 10.1093/ndt/gft216. Epub 2013 May 31.
• [10] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] 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.
• [17] 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.
• [18] 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.