Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU1AIEW)

• DOT Name: V-type proton ATPase 116 kDa subunit a 3 (TCIRG1)
• Synonyms: V-ATPase 116 kDa subunit a 3; Osteoclastic proton pump 116 kDa subunit; OC-116 kDa; OC116; T-cell immune regulator 1; T-cell immune response cDNA7 protein; TIRC7; Vacuolar proton translocating ATPase 116 kDa subunit a isoform 3
• Gene Name: TCIRG1
• Related Disease:
  Autosomal recessive osteopetrosis 1
  Infantile malignant osteopetrosis
  Autosomal dominant severe congenital neutropenia
  Autosomal recessive osteopetrosis 6
  Dysosteosclerosis
• UniProt ID: VPP3_HUMAN
• Pfam ID: PF01496
• Sequence:
  MGSMFRSEEVALVQLFLPTAAAYTCVSRLGELGLVEFRDLNASVSAFQRRFVVDVRRCEE
  LEKTFTFLQEEVRRAGLVLPPPKGRLPAPPPRDLLRIQEETERLAQELRDVRGNQQALRA
  QLHQLQLHAAVLRQGHEPQLAAAHTDGASERTPLLQAPGGPHQDLRVNFVAGAVEPHKAP
  ALERLLWRACRGFLIASFRELEQPLEHPVTGEPATWMTFLISYWGEQIGQKIRKITDCFH
  CHVFPFLQQEEARLGALQQLQQQSQELQEVLGETERFLSQVLGRVLQLLPPGQVQVHKMK
  AVYLALNQCSVSTTHKCLIAEAWCSVRDLPALQEALRDSSMEEGVSAVAHRIPCRDMPPT
  LIRTNRFTASFQGIVDAYGVGRYQEVNPAPYTIITFPFLFAVMFGDVGHGLLMFLFALAM
  VLAENRPAVKAAQNEIWQTFFRGRYLLLLMGLFSIYTGFIYNECFSRATSIFPSGWSVAA
  MANQSGWSDAFLAQHTMLTLDPNVTGVFLGPYPFGIDPIWSLAANHLSFLNSFKMKMSVI
  LGVVHMAFGVVLGVFNHVHFGQRHRLLLETLPELTFLLGLFGYLVFLVIYKWLCVWAARA
  ASAPSILIHFINMFLFSHSPSNRLLYPRQEVVQATLVVLALAMVPILLLGTPLHLLHRHR
  RRLRRRPADRQEENKAGLLDLPDASVNGWSSDEEKAGGLDDEEEAELVPSEVLMHQAIHT
  IEFCLGCVSNTASYLRLWALSLAHAQLSEVLWAMVMRIGLGLGREVGVAAVVLVPIFAAF
  AVMTVAILLVMEGLSAFLHALRLHWVEFQNKFYSGTGYKLSPFTFAATDD
• 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. Seems to be directly involved in T-cell activation.
• Tissue Specificity: Isoform long is highly expressed in osteoclastomas. Isoform short is highly expressed in thymus.
• 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)
  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:ENSG00000110719-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive osteopetrosis 1	DISU8DQM	Definitive	Autosomal recessive	[1]
Infantile malignant osteopetrosis	DIS8C3LZ	Definitive	Autosomal recessive	[1]
Autosomal dominant severe congenital neutropenia	DISZC7BV	Supportive	Autosomal dominant	[2]
Autosomal recessive osteopetrosis 6	DIS5LWCT	Supportive	Autosomal recessive	[3]
Dysosteosclerosis	DISYAE0Y	Supportive	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[11]
Aspirin	DM672AH	Approved	Aspirin increases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of V-type proton ATPase 116 kDa subunit a 3 (TCIRG1).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] TCIRG1-associated congenital neutropenia. Hum Mutat. 2014 Jul;35(7):824-7. doi: 10.1002/humu.22563. Epub 2014 May 21.
• [3] As little as needed: the extraordinary case of a mild recessive osteopetrosis owing to a novel splicing hypomorphic mutation in the TCIRG1 gene. J Bone Miner Res. 2014 Jul;29(7):1646-50. doi: 10.1002/jbmr.2203.
• [4] Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. Bone. 2019 Mar;120:495-503. doi: 10.1016/j.bone.2018.12.002. Epub 2018 Dec 8.
• [5] 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.
• [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] 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.
• [9] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.