Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMOZJO0)

• DOT Name: V-type proton ATPase subunit d 2 (ATP6V0D2)
• Synonyms: V-ATPase subunit d 2; Vacuolar proton pump subunit d 2
• Gene Name: ATP6V0D2
• Related Disease:
  Advanced cancer
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Invasive candidiasis
  Melanoma
  Neoplasm
  Bacterial infection
  Ehlers-Danlos syndrome
  Osteopetrosis
• UniProt ID: VA0D2_HUMAN
• Pfam ID: PF01992
• Sequence:
  MLEGAELYFNVDHGYLEGLVRGCKASLLTQQDYINLVQCETLEDLKIHLQTTDYGNFLAN
  HTNPLTVSKIDTEMRKRLCGEFEYFRNHSLEPLSTFLTYMTCSYMIDNVILLMNGALQKK
  SVKEILGKCHPLGRFTEMEAVNIAETPSDLFNAILIETPLAPFFQDCMSENALDELNIEL
  LRNKLYKSYLEAFYKFCKNHGDVTAEVMCPILEFEADRRAFIITLNSFGTELSKEDRETL
  YPTFGKLYPEGLRLLAQAEDFDQMKNVADHYGVYKPLFEAVGGSGGKTLEDVFYEREVQM
  NVLAFNRQFHYGVFYAYVKLKEQEIRNIVWIAECISQRHRTKINSYIPIL
• 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. Regulator of osteoclast fusion and bone formation.
• Tissue Specificity: Kidney, osteoclast and lung.
• 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:
  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:HS07458-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
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[2]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[2]
Invasive candidiasis	DIS5EI0L	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[5]
Ehlers-Danlos syndrome	DISSVBRR	Limited	Autosomal recessive	[6]
Osteopetrosis	DIS7GHNM	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenytoin	DMNOKBV	Approved	V-type proton ATPase subunit d 2 (ATP6V0D2) increases the Hypersensitivity ADR of Phenytoin.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of V-type proton ATPase subunit d 2 (ATP6V0D2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of V-type proton ATPase subunit d 2 (ATP6V0D2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of V-type proton ATPase subunit d 2 (ATP6V0D2).	[17]

References

• [1] Elevated expression of the V-ATPase D2 subunit triggers increased energy metabolite levels in Kras(G12D) -driven cancer cells.J Cell Biochem. 2019 Jul;120(7):11690-11701. doi: 10.1002/jcb.28448. Epub 2019 Feb 11.
• [2] Expression of acidosis-dependent genes in human cancer nests.Mol Clin Oncol. 2014 Nov;2(6):1160-1166. doi: 10.3892/mco.2014.344. Epub 2014 Jul 11.
• [3] 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.
• [4] Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2-mediated tumor progression.J Clin Invest. 2019 Feb 1;129(2):631-646. doi: 10.1172/JCI123027. Epub 2019 Jan 7.
• [5] The macrophage-specific V-ATPase subunit ATP6V0D2 restricts inflammasome activation and bacterial infection by facilitating autophagosome-lysosome fusion.Autophagy. 2019 Jun;15(6):960-975. doi: 10.1080/15548627.2019.1569916. Epub 2019 Jan 29.
• [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] ClC-7/Ostm1 contribute to the ability of tea polyphenols to maintain bone homeostasis in C57BL/6 mice, protecting against fluorosis.Int J Mol Med. 2017 May;39(5):1155-1163. doi: 10.3892/ijmm.2017.2933. Epub 2017 Mar 22.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [17] 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.
• [18] Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.