Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSM7ML1)

• DOT Name: V-type proton ATPase subunit C 2 (ATP6V1C2)
• Synonyms: V-ATPase subunit C 2; Vacuolar proton pump subunit C 2
• Gene Name: ATP6V1C2
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
• UniProt ID: VATC2_HUMAN
• Pfam ID: PF03223
• Sequence:
  MSEFWLISAPGDKENLQALERMNTVTSKSNLSYNTKFAIPDFKVGTLDSLVGLSDELGKL
  DTFAESLIRRMAQSVVEVMEDSKGKVQEHLLANGVDLTSFVTHFEWDMAKYPVKQPLVSV
  VDTIAKQLAQIEMDLKSRTAAYNTLKTNLENLEKKSMGNLFTRTLSDIVSKEDFVLDSEY
  LVTLLVIVPKPNYSQWQKTYESLSDMVVPRSTKLITEDKEGGLFTVTLFRKVIEDFKTKA
  KENKFTVREFYYDEKEIEREREEMARLLSDKKQQYQTSCVALKKGSSTFPDHKVKVTPLG
  NPDRPAAGQTDRERESEGEGEGPLLRWLKVNFSEAFIAWIHIKALRVFVESVLRYGLPVN
  FQAVLLQPHKKSSTKRLREVLNSVFRHLDEVAATSILDASVEIPGLQLNNQDYFPYVYFH
  IDLSLLD
• 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. Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity.
• Tissue Specificity: Kidney and placenta.
• 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:
  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:HS07123-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	V-type proton ATPase subunit C 2 (ATP6V1C2) affects the response to substance of Cisplatin.	[13]

9 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 C 2 (ATP6V1C2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[11]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate affects the expression of V-type proton ATPase subunit C 2 (ATP6V1C2).	[12]

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 C 2 (ATP6V1C2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of V-type proton ATPase subunit C 2 (ATP6V1C2).	[9]

References

• [1] Identification of key biomarkers involved in osteosarcoma using altered modules.Genet Mol Res. 2016 Aug 26;15(3). doi: 10.4238/gmr.15038277.
• [2] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] 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.
• [7] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [8] 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.
• [9] 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.
• [10] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Molecular mechanism of di-n-butyl phthalate promotion of bladder cancer development. Toxicol In Vitro. 2023 Feb;86:105508. doi: 10.1016/j.tiv.2022.105508. Epub 2022 Nov 12.
• [13] Role of transporter genes in cisplatin resistance. In Vivo. 2008 May-Jun;22(3):279-83.