Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4ALYU4)

• DOT Name: Voltage-gated hydrogen channel 1 (HVCN1)
• Synonyms: Hydrogen voltage-gated channel 1; HV1; Voltage sensor domain-only protein
• Gene Name: HVCN1
• Related Disease:
  Adult lymphoma
  Autoimmune disease
  Follicular lymphoma
  Lymphoma
  Nephritis
  Osteosarcoma
  Pediatric lymphoma
  Breast cancer
  Breast carcinoma
  Small lymphocytic lymphoma
• UniProt ID: HVCN1_HUMAN
• PDB ID: 3A2A; 5OQK
• Pfam ID: PF00520 ; PF16799
• Sequence:
  MATWDEKAVTRRAKVAPAERMSKFLRHFTVVGDDYHAWNINYKKWENEEEEEEEEQPPPT
  PVSGEEGRAAAPDVAPAPGPAPRAPLDFRGMLRKLFSSHRFQVIIICLVVLDALLVLAEL
  ILDLKIIQPDKNNYAAMVFHYMSITILVFFMMEIIFKLFVFRLEFFHHKFEILDAVVVVV
  SFILDIVLLFQEHQFEALGLLILLRLWRVARIINGIIISVKTRSERQLLRLKQMNVQLAA
  KIQHLEFSCSEKEQEIERLNKLLRQHGLLGEVN
• Function: Voltage-gated proton-selective channel that conducts outward proton currents in response to intracellular acidification. Lacks a canonical ion-channel pore domain and mediates proton permeability via its voltage sensor domain. Appears to play a dominant role in regulation of CO2/HCO3(-)/H(+) equilibrium in sperm flagellum. Prevents the acidification resulting from HCO3(-) synthesis and thus sustains high HCO3(-) levels inside sperm for capacitation. Provides for proton efflux that compensates for electron charge generated by NADPH oxidase activity either in the extracellular or phagosomal compartments, thus enabling the production of high levels of bactericidal reactive oxygen species during the respiratory burst. Opens when the pH of airway surface liquid exceeds 7 and contributes to respiratory epithelial acid secretion to maintain pH in the mucosa.
• Tissue Specificity: Enriched in immune tissues, such as lymph nodes, B-lymphocytes, monocytes and spleen . Expressed in spermatozoa . Expressed in respiratory epithelial cells .
• Reactome Pathway:
  Sperm Motility And Taxes (R-HSA-1300642)
  Neutrophil degranulation (R-HSA-6798695)
  ROS and RNS production in phagocytes (R-HSA-1222556)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Follicular lymphoma	DISVEUR6	Strong	Biomarker	[1]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[1]
Nephritis	DISQZQ70	Strong	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[3]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[4]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[4]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[5]

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 Voltage-gated hydrogen channel 1 (HVCN1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Voltage-gated hydrogen channel 1 (HVCN1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Voltage-gated hydrogen channel 1 (HVCN1).	[15]

References

• [1] Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma.Blood. 2017 Jan 26;129(4):473-483. doi: 10.1182/blood-2016-07-729954. Epub 2016 Nov 14.
• [2] Autoimmune disorder phenotypes in Hvcn1-deficient mice.Biochem J. 2013 Mar 1;450(2):295-301. doi: 10.1042/BJ20121188.
• [3] Mutations in the mitochondrial DNA D-Loop region occur frequently in human osteosarcoma.Cancer Lett. 2006 Jul 28;239(1):151-5. doi: 10.1016/j.canlet.2005.08.008. Epub 2005 Oct 20.
• [4] Clinicopathological and biological significance of human voltage-gated proton channel Hv1 protein overexpression in breast cancer.J Biol Chem. 2012 Apr 20;287(17):13877-88. doi: 10.1074/jbc.M112.345280. Epub 2012 Feb 24.
• [5] Enhanced activation of an amino-terminally truncated isoform of the voltage-gated proton channel HVCN1 enriched in malignant B cells.Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):18078-83. doi: 10.1073/pnas.1411390111. Epub 2014 Nov 25.
• [6] 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.
• [7] 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.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.