Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP16WIW)

• DOT Name: Vacuolar protein sorting-associated protein 18 homolog
• Synonyms: hVPS18
• Gene Name: VPS18
• Related Disease: Leukodystrophy
• UniProt ID: VPS18_HUMAN
• Pfam ID: PF05131
• Sequence:
  MASILDEYENSLSRSAVLQPGCPSVGIPHSGYVNAQLEKEVPIFTKQRIDFTPSERITSL
  VVSSNQLCMSLGKDTLLRIDLGKANEPNHVELGRKDDAKVHKMFLDHTGSHLLIALSSTE
  VLYVNRNGQKVRPLARWKGQLVESVGWNKALGTESSTGPILVGTAQGHIFEAELSASEGG
  LFGPAPDLYFRPLYVLNEEGGPAPVCSLEAERGPDGRSFVIATTRQRLFQFIGRAAEGAE
  AQGFSGLFAAYTDHPPPFREFPSNLGYSELAFYTPKLRSAPRAFAWMMGDGVLYGALDCG
  RPDSLLSEERVWEYPEGVGPGASPPLAIVLTQFHFLLLLADRVEAVCTLTGQVVLRDHFL
  EKFGPLKHMVKDSSTGQLWAYTERAVFRYHVQREARDVWRTYLDMNRFDLAKEYCRERPD
  CLDTVLAREADFCFRQRRYLESARCYALTQSYFEEIALKFLEARQEEALAEFLQRKLASL
  KPAERTQATLLTTWLTELYLSRLGALQGDPEALTLYRETKECFRTFLSSPRHKEWLFASR
  ASIHELLASHGDTEHMVYFAVIMQDYERVVAYHCQHEAYEEALAVLARHRDPQLFYKFSP
  ILIRHIPRQLVDAWIEMGSRLDARQLIPALVNYSQGGEVQQVSQAIRYMEFCVNVLGETE
  QAIHNYLLSLYARGRPDSLLAYLEQAGASPHRVHYDLKYALRLCAEHGHHRACVHVYKVL
  ELYEEAVDLALQVDVDLAKQCADLPEEDEELRKKLWLKIARHVVQEEEDVQTAMACLASC
  PLLKIEDVLPFFPDFVTIDHFKEAICSSLKAYNHHIQELQREMEEATASAQRIRRDLQEL
  RGRYGTVEPQDKCATCDFPLLNRPFYLFLCGHMFHADCLLQAVRPGLPAYKQARLEELQR
  KLGAAPPPAKGSARAKEAEGGAATAGPSREQLKADLDELVAAECVYCGELMIRSIDRPFI
  DPQRYEEEQLSWL
• 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 fusion of endosomes and autophagosomes with lysosomes. Involved in dendrite development of Pukinje cells.
• Tissue Specificity: Ubiquitous. Expression was highest in heart and low in lung.
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukodystrophy	DISVY1TT	No Known	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Vacuolar protein sorting-associated protein 18 homolog.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Vacuolar protein sorting-associated protein 18 homolog.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Vacuolar protein sorting-associated protein 18 homolog.	[13]

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 increases the methylation of Vacuolar protein sorting-associated protein 18 homolog.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Vacuolar protein sorting-associated protein 18 homolog.	[11]

References

• [1] Ablation of vacuole protein sorting 18 (Vps18) gene leads to neurodegeneration and impaired neuronal migration by disrupting multiple vesicle transport pathways to lysosomes. J Biol Chem. 2012 Sep 21;287(39):32861-73. doi: 10.1074/jbc.M112.384305. Epub 2012 Aug 1.
• [2] 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.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.