Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1IK0KA)

• DOT Name: V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1)
• Synonyms: V-ATPase 116 kDa subunit a 1; Clathrin-coated vesicle/synaptic vesicle proton pump 116 kDa subunit; Vacuolar adenosine triphosphatase subunit Ac116; Vacuolar proton pump subunit 1; Vacuolar proton translocating ATPase 116 kDa subunit a isoform 1
• Gene Name: ATP6V0A1
• Related Disease:
  Cryptococcosis
  Developmental and epileptic encephalopathy 104
  Encephalitis
  High blood pressure
  Neurodevelopmental disorder with epilepsy and brain atrophy
  Advanced cancer
  Colorectal carcinoma
  Colorectal neoplasm
  Complex neurodevelopmental disorder
• UniProt ID: VPP1_HUMAN
• PDB ID: 6WLW; 6WM2; 6WM3; 6WM4; 7U4T
• Pfam ID: PF01496
• Sequence:
  MGELFRSEEMTLAQLFLQSEAAYCCVSELGELGKVQFRDLNPDVNVFQRKFVNEVRRCEE
  MDRKLRFVEKEIRKANIPIMDTGENPEVPFPRDMIDLEANFEKIENELKEINTNQEALKR
  NFLELTELKFILRKTQQFFDEMADPDLLEESSSLLEPSEMGRGTPLRLGFVAGVINRERI
  PTFERMLWRVCRGNVFLRQAEIENPLEDPVTGDYVHKSVFIIFFQGDQLKNRVKKICEGF
  RASLYPCPETPQERKEMASGVNTRIDDLQMVLNQTEDHRQRVLQAAAKNIRVWFIKVRKM
  KAIYHTLNLCNIDVTQKCLIAEVWCPVTDLDSIQFALRRGTEHSGSTVPSILNRMQTNQT
  PPTYNKTNKFTYGFQNIVDAYGIGTYREINPAPYTIITFPFLFAVMFGDFGHGILMTLFA
  VWMVLRESRILSQKNENEMFSTVFSGRYIILLMGVFSMYTGLIYNDCFSKSLNIFGSSWS
  VRPMFTYNWTEETLRGNPVLQLNPALPGVFGGPYPFGIDPIWNIATNKLTFLNSFKMKMS
  VILGIIHMLFGVSLSLFNHIYFKKPLNIYFGFIPEIIFMTSLFGYLVILIFYKWTAYDAH
  TSENAPSLLIHFINMFLFSYPESGYSMLYSGQKGIQCFLVVVALLCVPWMLLFKPLVLRR
  QYLRRKHLGTLNFGGIRVGNGPTEEDAEIIQHDQLSTHSEDADEPSEDEVFDFGDTMVHQ
  AIHTIEYCLGCISNTASYLRLWALSLAHAQLSEVLWTMVIHIGLSVKSLAGGLVLFFFFT
  AFATLTVAILLIMEGLSAFLHALRLHWVEFQNKFYSGTGFKFLPFSFEHIREGKFEE
• 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 transports protons across cellular membranes. V-ATPase is responsible for the acidification of various organelles, such as lysosomes, endosomes, the trans-Golgi network, and secretory granules, including synaptic vesicles. In certain cell types, can be exported to the plasma membrane, where it is involved in the acidification of the extracellular environment. Required for assembly and activity of the vacuolar ATPase. Through its action on compartment acidification, plays an essential role in neuronal development in terms of integrity and connectivity of neurons.
• 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:
  Neutrophil degranulation (R-HSA-6798695)
  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:ENSG00000033627-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
Cryptococcosis	DISDYDTK	Strong	Biomarker	[1]
Developmental and epileptic encephalopathy 104	DISQTKGI	Strong	Autosomal dominant	[2]
Encephalitis	DISLD1RL	Strong	Genetic Variation	[1]
High blood pressure	DISY2OHH	Strong	Biomarker	[3]
Neurodevelopmental disorder with epilepsy and brain atrophy	DISC1CTY	Strong	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[4]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[4]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[11]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[18]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[19]

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 increases the methylation of V-type proton ATPase 116 kDa subunit a 1 (ATP6V0A1).	[14]

References

• [1] 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.
• [2] ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice. Nat Commun. 2021 Apr 8;12(1):2107. doi: 10.1038/s41467-021-22389-5.
• [3] A common genetic variant in the 3'-UTR of vacuolar H+-ATPase ATP6V0A1 creates a micro-RNA motif to alter chromogranin A processing and hypertension risk.Circ Cardiovasc Genet. 2011 Aug 1;4(4):381-9. doi: 10.1161/CIRCGENETICS.111.959767. Epub 2011 May 9.
• [4] POLR2F, ATP6V0A1 and PRNP expression in colorectal cancer: new molecules with prognostic significance?.Anticancer Res. 2008 Mar-Apr;28(2B):1221-7.
• [5] 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.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] Rifampicin attenuates rotenone-treated microglia inflammation via improving lysosomal function. Toxicol In Vitro. 2020 Mar;63:104690. doi: 10.1016/j.tiv.2019.104690. Epub 2019 Oct 22.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.