Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9GU2NW)

• DOT Name: V-type proton ATPase subunit d 1 (ATP6V0D1)
• Synonyms: V-ATPase subunit d 1; 32 kDa accessory protein; V-ATPase 40 kDa accessory protein; V-ATPase AC39 subunit; p39; Vacuolar proton pump subunit d 1
• Gene Name: ATP6V0D1
• Related Disease:
  Neoplasm
  Squamous cell carcinoma
  Age-related macular degeneration
  Alzheimer disease
  Brain disease
  Invasive candidiasis
  Lyme disease
  Schizophrenia
  Matthew-Wood syndrome
  Pancreatic cancer
  Choriocarcinoma
• UniProt ID: VA0D1_HUMAN
• PDB ID: 6WLW; 6WM2; 6WM3; 6WM4; 7U4T; 7UNF
• Pfam ID: PF01992
• Sequence:
  MSFFPELYFNVDNGYLEGLVRGLKAGVLSQADYLNLVQCETLEDLKLHLQSTDYGNFLAN
  EASPLTVSVIDDRLKEKMVVEFRHMRNHAYEPLASFLDFITYSYMIDNVILLITGTLHQR
  SIAELVPKCHPLGSFEQMEAVNIAQTPAELYNAILVDTPLAAFFQDCISEQDLDEMNIEI
  IRNTLYKAYLESFYKFCTLLGGTTADAMCPILEFEADRRAFIITINSFGTELSKEDRAKL
  FPHCGRLYPEGLAQLARADDYEQVKNVADYYPEYKLLFEGAGSNPGDKTLEDRFFEHEVK
  LNKLAFLNQFHFGVFYAFVKLKEQECRNIVWIAECIAQRHRAKIDNYIPIF
• 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. May play a role in coupling of proton transport and ATP hydrolysis. In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation. May play a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium.
• Tissue Specificity: Ubiquitous.
• 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)
  Viral carcinogenesis (hsa05203)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  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:HS08417-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Definitive	Biomarker	[1]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Brain disease	DIS6ZC3X	Strong	Biomarker	[3]
Invasive candidiasis	DIS5EI0L	Strong	Biomarker	[4]
Lyme disease	DISO70G5	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[6]
Matthew-Wood syndrome	DISA7HR7	moderate	Altered Expression	[7]
Pancreatic cancer	DISJC981	moderate	Biomarker	[7]
Choriocarcinoma	DISDBVNL	Limited	Biomarker	[8]

16 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 d 1 (ATP6V0D1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[16]
Selenium	DM25CGV	Approved	Selenium increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[17]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[24]
PP-242	DM2348V	Investigative	PP-242 increases the expression of V-type proton ATPase subunit d 1 (ATP6V0D1).	[25]

2 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 d 1 (ATP6V0D1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of V-type proton ATPase subunit d 1 (ATP6V0D1).	[20]

References

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• [2] Genome-wide analysis of disease progression in age-related macular degeneration.Hum Mol Genet. 2018 Mar 1;27(5):929-940. doi: 10.1093/hmg/ddy002.
• [3] Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease.Neurobiol Aging. 2005 Aug-Sep;26(8):1145-51. doi: 10.1016/j.neurobiolaging.2004.10.003. Epub 2004 Dec 22.
• [4] Roles of VPH2 and VMA6 in localization of V-ATPase subunits, cell wall functions and filamentous development in Candida albicans.Fungal Genet Biol. 2018 May;114:1-11. doi: 10.1016/j.fgb.2018.03.001. Epub 2018 Mar 6.
• [5] Proteomics in human disease: cancer, heart and infectious diseases.Electrophoresis. 1999 Jul;20(10):2100-10. doi: 10.1002/(SICI)1522-2683(19990701)20:10<2100::AID-ELPS2100>3.0.CO;2-D.
• [6] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [7] Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.Clin Cancer Res. 2011 Oct 1;17(19):6140-50. doi: 10.1158/1078-0432.CCR-10-2288. Epub 2011 Aug 8.
• [8] Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase.Biochem Biophys Res Commun. 2000 Dec 20;279(2):543-7. doi: 10.1006/bbrc.2000.4003.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [11] 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.
• [12] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Arsenic trioxide induces autophagic cell death in osteosarcoma cells via the ROS-TFEB signaling pathway. Biochem Biophys Res Commun. 2018 Jan 29;496(1):167-175. doi: 10.1016/j.bbrc.2018.01.018. Epub 2018 Jan 4.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] 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.
• [23] 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.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.