Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJGJ6QN)

• DOT Name: Vacuolar protein sorting-associated protein 41 homolog
• Synonyms: S53
• Gene Name: VPS41
• Related Disease:
  Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
  Spinocerebellar ataxia, autosomal recessive 29
• UniProt ID: VPS41_HUMAN
• Pfam ID: PF00637
• Sequence:
  MAEAEEQETGSLEESTDESEEEESEEEPKLKYERLSNGVTEILQKDAASCMTVHDKFLAL
  GTHYGKVYLLDVQGNITQKFDVSPVKINQISLDESGEHMGVCSEDGKVQVFGLYSGEEFH
  ETFDCPIKIIAVHPHFVRSSCKQFVTGGKKLLLFERSWMNRWKSAVLHEGEGNIRSVKWR
  GHLIAWANNMGVKIFDIISKQRITNVPRDDISLRPDMYPCSLCWKDNVTLIIGWGTSVKV
  CSVKERHASEMRDLPSRYVEIVSQFETEFYISGLAPLCDQLVVLSYVKEISEKTEREYCA
  RPRLDIIQPLSETCEEISSDALTVRGFQENECRDYHLEYSEGESLFYIVSPRDVVVAKER
  DQDDHIDWLLEKKKYEEALMAAEISQKNIKRHKILDIGLAYINHLVERGDYDIAARKCQK
  ILGKNAALWEYEVYKFKEIGQLKAISPYLPRGDPVLKPLIYEMILHEFLESDYEGFATLI
  REWPGDLYNNSVIVQAVRDHLKKDSQNKTLLKTLAELYTYDKNYGNALEIYLTLRHKDVF
  QLIHKHNLFSSIKDKIVLLMDFDSEKAVDMLLDNEDKISIKKVVEELEDRPELQHVYLHK
  LFKRDHHKGQRYHEKQISLYAEYDRPNLLPFLRDSTHCPLEKALEICQQRNFVEETVYLL
  SRMGNSRSALKMIMEELHDVDKAIEFAKEQDDGELWEDLILYSIDKPPFITGLLNNIGTH
  VDPILLIHRIKEGMEIPNLRDSLVKILQDYNLQILLREGCKKILVADSLSLLKKMHRTQM
  KGVLVDEENICESCLSPILPSDAAKPFSVVVFHCRHMFHKECLPMPSMNSAAQFCNICSA
  KNRGPGSAILEMKK
• Function: Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act in part as a core component of the putative HOPS endosomal tethering complex is 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. Involved in homotypic vesicle fusions between late endosomes and in heterotypic fusions between late endosomes and lysosomes implicated in degradation of endocytosed cargo. Required for fusion of autophagosomes with lysosomes. Links the HOPS complex to endosomal Rab7 via its association with RILP and to lysosomal membranes via its association with ARL8B, suggesting that these interactions may bring the compartments to close proximity for fusion. Involved in the direct trans-Golgi network to late endosomes transport of lysosomal membrane proteins independently of HOPS. Involved in sorting to the regulated secretory pathway presumably implicating the AP-3 adapter complex. May play a role in HOPS-independent function in the regulated secretory pathway.
• Tissue Specificity: Expressed in cerebral cortex and cerebellum. Highly expressed in Purkinje cells.
• 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
Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome	DIST4BWR	Supportive	Autosomal recessive	[1]
Spinocerebellar ataxia, autosomal recessive 29	DIS9BC64	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Vacuolar protein sorting-associated protein 41 homolog.	[7]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[8]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[10]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Vacuolar protein sorting-associated protein 41 homolog.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Vacuolar protein sorting-associated protein 41 homolog.	[9]

References

• [1] Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking. Brain. 2021 Apr 12;144(3):769-780. doi: 10.1093/brain/awaa459.
• [2] Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities. Ann Neurol. 2020 Nov;88(5):867-877. doi: 10.1002/ana.25879. Epub 2020 Sep 21.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. Eur Rev Med Pharmacol Sci. 2014;18(24):3877-88.
• [7] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [8] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [9] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.