Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2C3JRN)

• DOT Name: von Hippel-Lindau disease tumor suppressor
• Synonyms: Protein G7; pVHL
• Gene Name: VHL
• Related Disease:
  Von hippel-lindau disease
  Chuvash polycythemia
  Renal cell carcinoma
  Hereditary pheochromocytoma-paraganglioma
• UniProt ID: VHL_HUMAN
• PDB ID: 1LM8 ; 1LQB ; 1VCB ; 3ZRC ; 3ZRF ; 3ZTC ; 3ZTD ; 3ZUN ; 4AJY ; 4AWJ ; 4B95 ; 4B9K ; 4BKS ; 4BKT ; 4W9C ; 4W9D ; 4W9E ; 4W9F ; 4W9G ; 4W9H ; 4W9I ; 4W9J ; 4W9K ; 4W9L ; 4WQO ; 5LLI ; 5N4W ; 5NVV ; 5NVW ; 5NVX ; 5NVY ; 5NVZ ; 5NW0 ; 5NW1 ; 5NW2 ; 5T35 ; 6BVB ; 6FMI ; 6FMJ ; 6FMK ; 6GFX ; 6GFY ; 6GFZ ; 6GMN ; 6GMQ ; 6GMR ; 6GMX ; 6HAX ; 6HAY ; 6HR2 ; 6I7Q ; 6I7R ; 6R6H ; 6R7F ; 6SIS ; 6ZHC ; 7CJB ; 7JTO ; 7JTP ; 7KHH ; 7PI4 ; 7Q2J ; 7S4E ; 7Z6L ; 7Z76 ; 7Z77 ; 7ZNT ; 8BB2 ; 8BB3 ; 8BB4 ; 8BB5 ; 8BDI ; 8BDJ ; 8BDL ; 8BDM ; 8BDN ; 8BDO ; 8BDS ; 8BDT ; 8BDX ; 8BEB ; 8C13 ; 8CQE ; 8CQK ; 8CQL ; 8EI3 ; 8EWV ; 8G1P ; 8G1Q ; 8P0F ; 8PC2 ; 8QU8 ; 8QVU ; 8QW6 ; 8QW7
• Pfam ID: PF01847 ; PF17211
• Sequence:
  MPRRAENWDEAEVGAEEAGVEEYGPEEDGGEESGAEESGPEESGPEELGAEEEMEAGRPR
  PVLRSVNSREPSQVIFCNRSPRVVLPVWLNFDGEPQPYPTLPPGTGRRIHSYRGHLWLFR
  DAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDI
  VRSLYEDLEDHPNVQKDLERLTQERIAHQRMGD
• Function: Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2. Acts as a negative regulator of mTORC1 by promoting ubiquitination and degradation of RPTOR.
• Tissue Specificity: Expressed in the adult and fetal brain and kidney.
• KEGG Pathway:
  HIF-1 sig.ling pathway (hsa04066)
  Ubiquitin mediated proteolysis (hsa04120)
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Neddylation (R-HSA-8951664)
  Replication of the SARS-CoV-1 genome (R-HSA-9682706)
  Replication of the SARS-CoV-2 genome (R-HSA-9694686)
  RHOBTB3 ATPase cycle (R-HSA-9706019)
  Antigen processing (R-HSA-983168)
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Von hippel-lindau disease	DIS6ZFQQ	Definitive	Autosomal dominant	[1]
Chuvash polycythemia	DISSJ1BG	Strong	Autosomal recessive	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Autosomal dominant	[2]
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of von Hippel-Lindau disease tumor suppressor.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of von Hippel-Lindau disease tumor suppressor.	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of von Hippel-Lindau disease tumor suppressor.	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of von Hippel-Lindau disease tumor suppressor.	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of von Hippel-Lindau disease tumor suppressor.	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of von Hippel-Lindau disease tumor suppressor.	[10]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of von Hippel-Lindau disease tumor suppressor.	[11]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of von Hippel-Lindau disease tumor suppressor.	[12]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of von Hippel-Lindau disease tumor suppressor.	[12]
Sodium chloride	DMM3950	Approved	Sodium chloride increases the expression of von Hippel-Lindau disease tumor suppressor.	[13]

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 von Hippel-Lindau disease tumor suppressor.	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of von Hippel-Lindau disease tumor suppressor.	[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] 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] Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet. 1997 Jul;6(7):1051-6. doi: 10.1093/hmg/6.7.1051.
• [4] 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.
• [5] 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.
• [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] Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol. 2004 Jan;11(1):63-9. doi: 10.1128/cdli.11.1.63-69.2004.
• [8] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol Cell Biol. 2006 Nov;26(22):8572-85.
• [11] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [12] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [13] Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells. Nanotoxicology. 2014 Aug;8(5):485-507.
• [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.