Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4JDG0W)

• DOT Name: V-type proton ATPase subunit D (ATP6V1D)
• Synonyms: V-ATPase subunit D; V-ATPase 28 kDa accessory protein; Vacuolar proton pump subunit D
• Gene Name: ATP6V1D
• Related Disease: Chronic obstructive pulmonary disease
• UniProt ID: VATD_HUMAN
• PDB ID: 6WLZ; 6WM2; 6WM3; 6WM4; 7U4T; 7UNF
• Pfam ID: PF01813
• Sequence:
  MSGKDRIEIFPSRMAQTIMKARLKGAQTGRNLLKKKSDALTLRFRQILKKIIETKMLMGE
  VMREAAFSLAEAKFTAGDFSTTVIQNVNKAQVKIRAKKDNVAGVTLPVFEHYHEGTDSYE
  LTGLARGGEQLAKLKRNYAKAVELLVELASLQTSFVTLDEAIKITNRRVNAIEHVIIPRI
  ERTLAYIITELDEREREEFYRLKKIQEKKKILKEKSEKDLEQRRAAGEVLEPANLLAEEK
  DEDLLFE
• Function: 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. May play a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium.
• 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:
  Neutrophil degranulation (R-HSA-6798695)
  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:HS02107-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[1]

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 (ATP6V1D).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of V-type proton ATPase subunit D (ATP6V1D).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of V-type proton ATPase subunit D (ATP6V1D).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of V-type proton ATPase subunit D (ATP6V1D).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of V-type proton ATPase subunit D (ATP6V1D).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase subunit D (ATP6V1D).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of V-type proton ATPase subunit D (ATP6V1D).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of V-type proton ATPase subunit D (ATP6V1D).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of V-type proton ATPase subunit D (ATP6V1D).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of V-type proton ATPase subunit D (ATP6V1D).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of V-type proton ATPase subunit D (ATP6V1D).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of V-type proton ATPase subunit D (ATP6V1D).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of V-type proton ATPase subunit D (ATP6V1D).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of V-type proton ATPase subunit D (ATP6V1D).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of V-type proton ATPase subunit D (ATP6V1D).	[17]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of V-type proton ATPase subunit D (ATP6V1D).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of V-type proton ATPase subunit D (ATP6V1D).	[14]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.