Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1CZDZU)

• DOT Name: Vacuolar protein sorting-associated protein 4A
• Synonyms: EC 3.6.4.6; Protein SKD2; VPS4-1; hVPS4
• Gene Name: VPS4A
• Related Disease:
  Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome
  Intellectual disability
• UniProt ID: VPS4A_HUMAN
• PDB ID: 1YXR; 2JQ9; 2K3W
• EC Number: 3.6.4.6
• Pfam ID: PF00004 ; PF17862 ; PF04212 ; PF09336
• Sequence:
  MTTSTLQKAIDLVTKATEEDKAKNYEEALRLYQHAVEYFLHAIKYEAHSDKAKESIRAKC
  VQYLDRAEKLKDYLRSKEKHGKKPVKENQSEGKGSDSDSEGDNPEKKKLQEQLMGAVVME
  KPNIRWNDVAGLEGAKEALKEAVILPIKFPHLFTGKRTPWRGILLFGPPGTGKSYLAKAV
  ATEANNSTFFSVSSSDLMSKWLGESEKLVKNLFELARQHKPSIIFIDEVDSLCGSRNENE
  SEAARRIKTEFLVQMQGVGNNNDGTLVLGATNIPWVLDSAIRRRFEKRIYIPLPEEAARA
  QMFRLHLGSTPHNLTDANIHELARKTEGYSGADISIIVRDSLMQPVRKVQSATHFKKVCG
  PSRTNPSMMIDDLLTPCSPGDPGAMEMTWMDVPGDKLLEPVVCMSDMLRSLATTRPTVNA
  DDLLKVKKFSEDFGQES
• Function: Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their 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. It is required for proper accomplishment of various processes including the regulation of endosome size, primary cilium organization, mitotic spindle organization, chromosome segregation, and nuclear envelope sealing and spindle disassembly during anaphase. Involved in cytokinesis: retained at the midbody by ZFYVE19/ANCHR and CHMP4C until abscission checkpoint signaling is terminated at late cytokinesis. It is then released following dephosphorylation of CHMP4C, leading to abscission. VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan. Critical for normal erythroblast cytokinesis and correct erythropoiesis ; (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)
  HCMV Late Events (R-HSA-9610379)
  Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)
  Budding and maturation of HIV virion (R-HSA-162588)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome	DISUJXFQ	Strong	Autosomal dominant	[1]
Intellectual disability	DISMBNXP	Limited	Autosomal dominant	[2]

8 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 4A.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vacuolar protein sorting-associated protein 4A.	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Vacuolar protein sorting-associated protein 4A.	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Vacuolar protein sorting-associated protein 4A.	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Vacuolar protein sorting-associated protein 4A.	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Vacuolar protein sorting-associated protein 4A.	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Vacuolar protein sorting-associated protein 4A.	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Vacuolar protein sorting-associated protein 4A.	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Vacuolar protein sorting-associated protein 4A.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Vacuolar protein sorting-associated protein 4A.	[11]

References

• [1] De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014 Oct 30;10(10):e1004772. doi: 10.1371/journal.pgen.1004772. eCollection 2014 Oct.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [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] 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.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] 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.