Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6FLMAN)

• DOT Name: Vacuolar protein sorting-associated protein 4B
• Synonyms: EC 3.6.4.6; Cell migration-inducing gene 1 protein; Suppressor of K(+) transport growth defect 1; Protein SKD1
• Gene Name: VPS4B
• Related Disease: Dentin dysplasia type I
• UniProt ID: VPS4B_HUMAN
• PDB ID: 1WR0; 1XWI; 2CPT; 2JQH; 2JQK; 4U7Y; 7L9X
• EC Number: 3.6.4.6
• Pfam ID: PF00004 ; PF17862 ; PF04212 ; PF09336
• Sequence:
  MSSTSPNLQKAIDLASKAAQEDKAGNYEEALQLYQHAVQYFLHVVKYEAQGDKAKQSIRA
  KCTEYLDRAEKLKEYLKNKEKKAQKPVKEGQPSPADEKGNDSDGEGESDDPEKKKLQNQL
  QGAIVIERPNVKWSDVAGLEGAKEALKEAVILPIKFPHLFTGKRTPWRGILLFGPPGTGK
  SYLAKAVATEANNSTFFSISSSDLVSKWLGESEKLVKNLFQLARENKPSIIFIDEIDSLC
  GSRSENESEAARRIKTEFLVQMQGVGVDNDGILVLGATNIPWVLDSAIRRRFEKRIYIPL
  PEPHARAAMFKLHLGTTQNSLTEADFRELGRKTDGYSGADISIIVRDALMQPVRKVQSAT
  HFKKVRGPSRADPNHLVDDLLTPCSPGDPGAIEMTWMDVPGDKLLEPVVSMSDMLRSLSN
  TKPTVNEHDLLKLKKFTEDFGQEG
• Function: Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan ; (Microbial infection) In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses).
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Endocytosis (hsa04144)
  Necroptosis (hsa04217)
• Reactome Pathway:
  Endosomal Sorting Complex Required For Transport (ESCRT) (R-HSA-917729)
  Budding and maturation of HIV virion (R-HSA-162588)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dentin dysplasia type I	DISS0DLW	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vacuolar protein sorting-associated protein 4B.	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Vacuolar protein sorting-associated protein 4B.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vacuolar protein sorting-associated protein 4B.	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Vacuolar protein sorting-associated protein 4B.	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Vacuolar protein sorting-associated protein 4B.	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Vacuolar protein sorting-associated protein 4B.	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Vacuolar protein sorting-associated protein 4B.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Vacuolar protein sorting-associated protein 4B.	[9]

References

• [1] A splicing mutation in VPS4B causes dentin dysplasia I. J Med Genet. 2016 Sep;53(9):624-33. doi: 10.1136/jmedgenet-2015-103619. Epub 2016 May 31.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.