Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJUZSO1)

• DOT Name: Vacuolar protein sorting-associated protein 53 homolog
• Gene Name: VPS53
• Related Disease:
  Pontocerebellar hypoplasia type 2E
  Pontocerebellar hypoplasia, type 13
  Obsolete progressive cerebello-cerebral atrophy
• UniProt ID: VPS53_HUMAN
• Pfam ID: PF16854 ; PF04100
• Sequence:
  MMEEEELEFVEELEAVLQLTPEVQLAIEQVFPSQDPLDRADFNAVEYINTLFPTEQSLAN
  IDEVVNKIRLKIRRLDDNIRTVVRGQTNVGQDGRQALEEAQKAIQQLFGKIKDIKDKAEK
  SEQMVKEITRDIKQLDHAKRHLTTSITTLNHLHMLAGGVDSLEAMTRRRQYGEVANLLQG
  VMNVLEHFHKYMGIPQIRQLSERVKAAQTELGQQILADFEEAFPSQGTKRPGGPSNVLRD
  ACLVANILDPRIKQEIIKKFIKQHLSEYLVLFQENQDVAWLDKIDRRYAWIKRQLVDYEE
  KYGRMFPREWCMAERIAVEFCHVTRAELAKIMRTRAKEIEVKLLLFAIQRTTNFEGFLAK
  RFSGCTLTDGTLKKLESPPPSTNPFLEDEPTPEMEELATEKGDLDQPKKPKAPDNPFHGI
  VSKCFEPHLYVYIESQDKNLGELIDRFVADFKAQGPPKPNTDEGGAVLPSCADLFVYYKK
  CMVQCSQLSTGEPMIALTTIFQKYLREYAWKILSGNLPKTTTSSGGLTISSLLKEKEGSE
  VAKFTLEELCLICNILSTAEYCLATTQQLEEKLKEKVDVSLIERINLTGEMDTFSTVISS
  SIQLLVQDLDAACDPALTAMSKMQWQNVEHVGDQSPYVTSVILHIKQNVPIIRDNLASTR
  KYFTQFCVKFANSFIPKFITHLFKCKPISMVGAEQLLLDTHSLKMVLLDLPSISSQVVRK
  APASYTKIVVKGMTRAEMILKVVMAPHEPLVVFVDNYIKLLTDCNTETFQKILDMKGLKR
  SEQSSMLELLRQRLPAPPSGAESSGSLSLTAPTPEQESSRIRKLEKLIKKRL
• Function: Acts as a component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN). The GARP complex is required for the maintenance of the cycling of mannose 6-phosphate receptors between the TGN and endosomes, this cycling is necessary for proper lysosomal sorting of acid hydrolases such as CTSD. Acts as a component of the EARP complex that is involved in endocytic recycling. The EARP complex associates with Rab4-positive endosomes and promotes recycling of internalized transferrin receptor (TFRC) to the plasma membrane.
• Reactome Pathway: Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pontocerebellar hypoplasia type 2E	DISRTJAA	Strong	Autosomal recessive	[1]
Pontocerebellar hypoplasia, type 13	DISWPQUM	Strong	Autosomal recessive	[2]
Obsolete progressive cerebello-cerebral atrophy	DISPEWML	Supportive	Autosomal recessive	[1]

4 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 53 homolog.	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Vacuolar protein sorting-associated protein 53 homolog.	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Vacuolar protein sorting-associated protein 53 homolog.	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Vacuolar protein sorting-associated protein 53 homolog.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Vacuolar protein sorting-associated protein 53 homolog.	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Vacuolar protein sorting-associated protein 53 homolog.	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Vacuolar protein sorting-associated protein 53 homolog.	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Vacuolar protein sorting-associated protein 53 homolog.	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Vacuolar protein sorting-associated protein 53 homolog.	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Vacuolar protein sorting-associated protein 53 homolog.	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Vacuolar protein sorting-associated protein 53 homolog.	[13]

References

• [1] VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2). J Med Genet. 2014 May;51(5):303-8. doi: 10.1136/jmedgenet-2013-101823. Epub 2014 Feb 27.
• [2] HCCS1 overexpression induces apoptosis via cathepsin D and intracellular calcium, and HCCS1 disruption in mice causes placental abnormality. Cell Death Differ. 2008 Sep;15(9):1481-90. doi: 10.1038/cdd.2008.73. Epub 2008 May 30.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [6] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [7] 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.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [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.
• [10] 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.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [12] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.