Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX17GQ9)

• DOT Name: V-type proton ATPase subunit H (ATP6V1H)
• Synonyms: V-ATPase subunit H; Nef-binding protein 1; NBP1; Protein VMA13 homolog; V-ATPase 50/57 kDa subunits; Vacuolar proton pump subunit H; Vacuolar proton pump subunit SFD
• Gene Name: ATP6V1H
• Related Disease:
  Alzheimer disease
  Blindness
  Non-insulin dependent diabetes
  Rheumatoid arthritis
  Sorsby fundus dystrophy
  Type-1/2 diabetes
  Osteoporosis
  Stroke
• UniProt ID: VATH_HUMAN
• PDB ID: 6WM2; 6WM3; 6WM4; 7FDA; 7FDB; 7FDC; 7U4T; 7UNF
• Pfam ID: PF11698 ; PF03224
• Sequence:
  MTKMDIRGAVDAAVPTNIIAAKAAEVRANKVNWQSYLQGQMISAEDCEFIQRFEMKRSPE
  EKQEMLQTEGSQCAKTFINLMTHICKEQTVQYILTMVDDMLQENHQRVSIFFDYARCSKN
  TAWPYFLPMLNRQDPFTVHMAARIIAKLAAWGKELMEGSDLNYYFNWIKTQLSSQKLRGS
  GVAVETGTVSSSDSSQYVQCVAGCLQLMLRVNEYRFAWVEADGVNCIMGVLSNKCGFQLQ
  YQMIFSIWLLAFSPQMCEHLRRYNIIPVLSDILQESVKEKVTRIILAAFRNFLEKSTERE
  TRQEYALAMIQCKVLKQLENLEQQKYDDEDISEDIKFLLEKLGESVQDLSSFDEYSSELK
  SGRLEWSPVHKSEKFWRENAVRLNEKNYELLKILTKLLEVSDDPQVLAVAAHDVGEYVRH
  YPRGKRVIEQLGGKQLVMNHMHHEDQQVRYNALLAVQKLMVHNWEYLGKQLQSEQPQTAA
  ARS
• 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 H is essential for V-ATPase activity, but not for the assembly of the complex. Involved in the endocytosis mediated by clathrin-coated pits, required for the formation of endosomes.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  mTOR sig.ling pathway (hsa04150)
  Sy.ptic vesicle cycle (hsa04721)
  Vibrio cholerae infection (hsa05110)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Tuberculosis (hsa05152)
  Human papillomavirus infection (hsa05165)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Nef Mediated CD4 Down-regulation (R-HSA-167590)
  Nef Mediated CD8 Down-regulation (R-HSA-182218)
  Insulin receptor recycling (R-HSA-77387)
  Transferrin endocytosis and recycling (R-HSA-917977)
  Blockage of phagosome acidification (R-HSA-9636467)
  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:HS00586-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Blindness	DISTIM10	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[3]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[4]
Sorsby fundus dystrophy	DISFVBJE	Strong	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[5]
Osteoporosis	DISF2JE0	Limited	Genetic Variation	[6]
Stroke	DISX6UHX	Limited	Altered Expression	[7]

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 H (ATP6V1H) affects the response to substance of Cisplatin.	[19]

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 H (ATP6V1H).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of V-type proton ATPase subunit H (ATP6V1H).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of V-type proton ATPase subunit H (ATP6V1H).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase subunit H (ATP6V1H).	[10]
Imatinib	DM7RJXL	Approved	Imatinib increases the expression of V-type proton ATPase subunit H (ATP6V1H).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of V-type proton ATPase subunit H (ATP6V1H).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of V-type proton ATPase subunit H (ATP6V1H).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of V-type proton ATPase subunit H (ATP6V1H).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of V-type proton ATPase subunit H (ATP6V1H).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of V-type proton ATPase subunit H (ATP6V1H).	[17]
PP-242	DM2348V	Investigative	PP-242 increases the expression of V-type proton ATPase subunit H (ATP6V1H).	[18]

References

• [1] Genome-wide association study identified ATP6V1H locus influencing cerebrospinal fluid BACE activity.BMC Med Genet. 2018 May 11;19(1):75. doi: 10.1186/s12881-018-0603-z.
• [2] A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth.Biochem Cell Biol. 1996;74(6):853-62. doi: 10.1139/o96-090.
• [3] ATP6V1H facilitates osteogenic differentiation in MC3T3-E1 cells via Akt/GSK3 signaling pathway.Organogenesis. 2019;15(2):43-54. doi: 10.1080/15476278.2019.1633869. Epub 2019 Jul 4.
• [4] Correlations Between Sagittal Spinal Balance and Quality of Life in Rheumatoid Arthritis.Clin Spine Surg. 2017 May;30(4):E412-E417. doi: 10.1097/BSD.0000000000000246.
• [5] Decreased expression of ATP6V1H in type 2 diabetes: a pilot report on the diabetes risk study in Mexican Americans.Biochem Biophys Res Commun. 2011 Sep 9;412(4):728-31. doi: 10.1016/j.bbrc.2011.08.041. Epub 2011 Aug 17.
• [6] ATP6V1H Deficiency Impairs Bone Development through Activation of MMP9 and MMP13.PLoS Genet. 2017 Feb 3;13(2):e1006481. doi: 10.1371/journal.pgen.1006481. eCollection 2017 Feb.
• [7] SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke.Aging Dis. 2018 Apr 1;9(2):287-295. doi: 10.14336/AD.2017.1112. eCollection 2018 Apr.
• [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] 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] Imatinib disturbs lysosomal function and morphology and impairs the activity of mTORC1 in human hepatocyte cell lines. Food Chem Toxicol. 2022 Apr;162:112869. doi: 10.1016/j.fct.2022.112869. Epub 2022 Feb 16.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [19] Role of transporter genes in cisplatin resistance. In Vivo. 2008 May-Jun;22(3):279-83.