Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT149Z7Q)

• DOT Name: V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4)
• Synonyms: V-ATPase 116 kDa isoform a 4; Vacuolar proton translocating ATPase 116 kDa subunit a isoform 4; Vacuolar proton translocating ATPase 116 kDa subunit a kidney isoform
• Gene Name: ATP6V0A4
• Related Disease:
  Clear cell renal carcinoma
  Cryptococcosis
  Distal renal tubular acidosis
  Encephalitis
  Nephrocalcinosis
  Renal tubular acidosis
  Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss
  Sensorineural hearing loss disorder
  Autosomal recessive distal renal tubular acidosis
• UniProt ID: VPP4_HUMAN
• PDB ID: 7UNF
• Pfam ID: PF01496
• Sequence:
  MVSVFRSEEMCLSQLFLQVEAAYCCVAELGELGLVQFKDLNMNVNSFQRKFVNEVRRCES
  LERILRFLEDEMQNEIVVQLLEKSPLTPLPREMITLETVLEKLEGELQEANQNQQALKQS
  FLELTELKYLLKKTQDFFETETNLADDFFTEDTSGLLELKAVPAYMTGKLGFIAGVINRE
  RMASFERLLWRICRGNVYLKFSEMDAPLEDPVTKEEIQKNIFIIFYQGEQLRQKIKKICD
  GFRATVYPCPEPAVERREMLESVNVRLEDLITVITQTESHRQRLLQEAAANWHSWLIKVQ
  KMKAVYHILNMCNIDVTQQCVIAEIWFPVADATRIKRALEQGMELSGSSMAPIMTTVQSK
  TAPPTFNRTNKFTAGFQNIVDAYGVGSYREINPAPYTIITFPFLFAVMFGDCGHGTVMLL
  AALWMILNERRLLSQKTDNEIWNTFFHGRYLILLMGIFSIYTGLIYNDCFSKSLNIFGSS
  WSVQPMFRNGTWNTHVMEESLYLQLDPAIPGVYFGNPYPFGIDPIWNLASNKLTFLNSYK
  MKMSVILGIVQMVFGVILSLFNHIYFRRTLNIILQFIPEMIFILCLFGYLVFMIIFKWCC
  FDVHVSQHAPSILIHFINMFLFNYSDSSNAPLYKHQQEVQSFFVVMALISVPWMLLIKPF
  ILRASHRKSQLQASRIQEDATENIEGDSSSPSSRSGQRTSADTHGALDDHGEEFNFGDVF
  VHQAIHTIEYCLGCISNTASYLRLWALSLAHAQLSEVLWTMVMNSGLQTRGWGGIVGVFI
  IFAVFAVLTVAILLIMEGLSAFLHALRLHWVEFQNKFYVGDGYKFSPFSFKHILDGTAEE
• Function: Subunit of the V0 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. Involved in normal vectorial acid transport into the urine by the kidney.
• Tissue Specificity: Expressed in adult and fetal kidney. Found in the inner ear.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Sy.ptic vesicle cycle (hsa04721)
  Collecting duct acid secretion (hsa04966)
  Vibrio cholerae infection (hsa05110)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Tuberculosis (hsa05152)
  Human papillomavirus infection (hsa05165)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Insulin receptor recycling (R-HSA-77387)
  Transferrin endocytosis and recycling (R-HSA-917977)
  Ion channel transport (R-HSA-983712)
  ROS and RNS production in phagocytes (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:ENSG00000105929-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[2]
Distal renal tubular acidosis	DISP6CYE	Strong	Genetic Variation	[3]
Encephalitis	DISLD1RL	Strong	Genetic Variation	[2]
Nephrocalcinosis	DIS5ZVJP	Strong	Genetic Variation	[4]
Renal tubular acidosis	DISE1NDR	Strong	Genetic Variation	[5]
Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss	DISH9VD5	Strong	Autosomal recessive	[6]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[7]
Autosomal recessive distal renal tubular acidosis	DISCJR4O	Supportive	Autosomal recessive	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4) affects the response to substance of Etoposide.	[17]

7 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 116 kDa subunit a 4 (ATP6V0A4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4).	[12]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4).	[16]

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 decreases the methylation of V-type proton ATPase 116 kDa subunit a 4 (ATP6V0A4).	[14]

References

• [1] FUT11 as a potential biomarker of clear cell renal cell carcinoma progression based on meta-analysis of gene expression data.Tumour Biol. 2014 Mar;35(3):2607-17. doi: 10.1007/s13277-013-1344-4. Epub 2013 Dec 8.
• [2] Multiple virulence factors of Cryptococcus neoformans are dependent on VPH1.Mol Microbiol. 2001 Nov;42(4):1121-31. doi: 10.1046/j.1365-2958.2001.02712.x.
• [3] A Family with Autosomal Dominant Distal Renal Tubular Acidosis Presents with Atypical Phenotype Caused by a Missence Mutation (R388C) of the Human Kidney Anion Exchanger.Nephron. 2019;141(3):207-212. doi: 10.1159/000495763. Epub 2018 Dec 14.
• [4] 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.
• [5] Molecular mechanisms of cutis laxa- and distal renal tubular acidosis-causing mutations in V-ATPase a subunits, ATP6V0A2 and ATP6V0A4.J Biol Chem. 2018 Feb 23;293(8):2787-2800. doi: 10.1074/jbc.M117.818872. Epub 2018 Jan 8.
• [6] 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.
• [7] Silencing of Odorant-Binding Protein Gene OBP3 Using RNA Interference Reduced Virus Transmission of Tomato Chlorosis Virus.Int J Mol Sci. 2019 Oct 9;20(20):4969. doi: 10.3390/ijms20204969.
• [8] 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.
• [9] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [10] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] 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.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] 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.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.