Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLWUS3T)

• DOT Name: Vacuolar protein sorting-associated protein 16 homolog
• Synonyms: hVPS16
• Gene Name: VPS16
• Related Disease:
  Dystonia 30
  Isolated dystonia
• UniProt ID: VPS16_HUMAN
• PDB ID: 4BX9
• Pfam ID: PF04840 ; PF04841
• Sequence:
  MDCYTANWNPLGDSAFYRKYELYSMDWDLKEELRDCLVAAAPYGGPIALLRNPWRKEKAA
  SVRPVLDIYSASGMPLASLLWKSGPVVSLGWSAEEELLCVQEDGAVLVYGLHGDFRRHFS
  MGNEVLQNRVLDARIFHTEFGSGVAILTGAHRFTLSANVGDLKLRRMPEVPGLQSAPSCW
  TVLCQDRVAHILLAVGPDLYLLDHAACSAVTPPGLAPGVSSFLQMAVSFTYRHLALFTDT
  GYIWMGTASLKEKLCEFNCNIRAPPKQMVWCSRPRSKERAVVVAWERRLMVVGDAPESIQ
  FVLDEDSYLVPELDGVRIFSRSTHEFLHEVPAASEEIFKIASMAPGALLLEAQKEYEKES
  QKADEYLREIQELGQLTQAVQQCIEAAGHEHQPDMQKSLLRAASFGKCFLDRFPPDSFVH
  MCQDLRVLNAVRDYHIGIPLTYSQYKQLTIQVLLDRLVLRRLYPLAIQICEYLRLPEVQG
  VSRILAHWACYKVQQKDVSDEDVARAINQKLGDTPGVSYSDIAARAYGCGRTELAIKLLE
  YEPRSGEQVPLLLKMKRSKLALSKAIESGDTDLVFTVLLHLKNELNRGDFFMTLRNQPMA
  LSLYRQFCKHQELETLKDLYNQDDNHQELGSFHIRASYAAEERIEGRVAALQTAADAFYK
  AKNEFAAKATEDQMRLLRLQRRLEDELGGQFLDLSLHDTVTTLILGGHNKRAEQLARDFR
  IPDKRLWWLKLTALADLEDWEELEKFSKSKKSPIGYLPFVEICMKQHNKYEAKKYASRVG
  PEQKVKALLLVGDVAQAADVAIEHRNEAELSLVLSHCTGATDGATADKIQRARAQAQKK
• Function: Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act as a core component of the putative HOPS and CORVET endosomal tethering complexes which are proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations. Required for recruitment of VPS33A to the HOPS complex. Required for fusion of endosomes and autophagosomes with lysosomes; the function is dependent on its association with VPS33A but not VPS33B. The function in autophagosome-lysosome fusion implicates STX17 but not UVRAG.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Efferocytosis (hsa04148)
  Salmonella infection (hsa05132)
• Reactome Pathway: SARS-CoV-2 modulates autophagy (R-HSA-9754560)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dystonia 30	DIS6NPU1	Strong	Autosomal dominant	[1]
Isolated dystonia	DISH6KEJ	Limited	Autosomal recessive	[2]

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 Vacuolar protein sorting-associated protein 16 homolog.	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Vacuolar protein sorting-associated protein 16 homolog.	[8]

5 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 16 homolog.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vacuolar protein sorting-associated protein 16 homolog.	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Vacuolar protein sorting-associated protein 16 homolog.	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Vacuolar protein sorting-associated protein 16 homolog.	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Vacuolar protein sorting-associated protein 16 homolog.	[9]

References

• [1] Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia. Sci Rep. 2016 May 12;6:25834. doi: 10.1038/srep25834.
• [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] 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.
• [4] 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.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] 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.
• [9] 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.