Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYZ2S9E)

• DOT Name: V-type proton ATPase catalytic subunit A (ATP6V1A)
• Synonyms: V-ATPase subunit A; EC 7.1.2.2; V-ATPase 69 kDa subunit; Vacuolar ATPase isoform VA68; Vacuolar proton pump subunit alpha
• Gene Name: ATP6V1A
• Related Disease:
  Epileptic encephalopathy, infantile or early childhood, 3
  Autosomal recessive cutis laxa type 2D
  Autosomal recessive cutis laxa type 2, classic type
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: VATA_HUMAN
• PDB ID: 6WLZ; 6WM2; 6WM3; 6WM4; 7U4T; 7UNF
• EC Number: 7.1.2.2
• Pfam ID: PF00006 ; PF02874 ; PF16886
• Sequence:
  MDFSKLPKILDEDKESTFGYVHGVSGPVVTACDMAGAAMYELVRVGHSELVGEIIRLEGD
  MATIQVYEETSGVSVGDPVLRTGKPLSVELGPGIMGAIFDGIQRPLSDISSQTQSIYIPR
  GVNVSALSRDIKWDFTPCKNLRVGSHITGGDIYGIVSENSLIKHKIMLPPRNRGTVTYIA
  PPGNYDTSDVVLELEFEGVKEKFTMVQVWPVRQVRPVTEKLPANHPLLTGQRVLDALFPC
  VQGGTTAIPGAFGCGKTVISQSLSKYSNSDVIIYVGCGERGNEMSEVLRDFPELTMEVDG
  KVESIMKRTALVANTSNMPVAAREASIYTGITLSEYFRDMGYHVSMMADSTSRWAEALRE
  ISGRLAEMPADSGYPAYLGARLASFYERAGRVKCLGNPEREGSVSIVGAVSPPGGDFSDP
  VTSATLGIVQVFWGLDKKLAQRKHFPSVNWLISYSKYMRALDEYYDKHFTEFVPLRTKAK
  EILQEEEDLAEIVQLVGKASLAETDKITLEVAKLIKDDFLQQNGYTPYDRFCPFYKTVGM
  LSNMIAFYDMARRAVETTAQSDNKITWSIIREHMGDILYKLSSMKFKDPLKDGEAKIKSD
  YAQLLEDMQNAFRSLED
• Function: Catalytic 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. 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 neurite development and synaptic connectivity ; (Microbial infection) Plays an important role in virion uncoating during Rabies virus replication after membrane fusion. Specifically, participates in the dissociation of incoming viral matrix M proteins uncoating through direct interaction.
• Tissue Specificity: High expression in the skin.
• 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:HS03781-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epileptic encephalopathy, infantile or early childhood, 3	DISIYU5W	Definitive	Autosomal dominant	[1]
Autosomal recessive cutis laxa type 2D	DISJUYUW	Strong	Autosomal recessive	[2]
Autosomal recessive cutis laxa type 2, classic type	DISMZ113	Supportive	Autosomal recessive	[3]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	V-type proton ATPase catalytic subunit A (ATP6V1A) affects the response to substance of Cisplatin.	[20]
Paclitaxel	DMLB81S	Approved	V-type proton ATPase catalytic subunit A (ATP6V1A) affects the response to substance of Paclitaxel.	[21]

3 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 catalytic subunit A (ATP6V1A).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of V-type proton ATPase catalytic subunit A (ATP6V1A).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of V-type proton ATPase catalytic subunit A (ATP6V1A).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[13]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[14]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[15]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of V-type proton ATPase catalytic subunit A (ATP6V1A).	[19]

References

• [1] De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy. Brain. 2018 Jun 1;141(6):1703-1718. doi: 10.1093/brain/awy092.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa. Am J Hum Genet. 2017 Feb 2;100(2):216-227. doi: 10.1016/j.ajhg.2016.12.010. Epub 2017 Jan 5.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells. J Steroid Biochem Mol Biol. 2003 May;85(1):1-8. doi: 10.1016/s0960-0760(03)00142-0.
• [13] 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.
• [14] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [15] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] 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.
• [20] Role of transporter genes in cisplatin resistance. In Vivo. 2008 May-Jun;22(3):279-83.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.