Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2M01JL)

• DOT Name: Vacuolar protein sorting-associated protein 51 homolog
• Synonyms: Another new gene 2 protein; Protein fat-free homolog
• Gene Name: VPS51
• Related Disease: Pontocerebellar hypoplasia, type 13
• UniProt ID: VPS51_HUMAN
• PDB ID: 4J2C
• Pfam ID: PF08700
• Sequence:
  MAAAAAAGPSPGSGPGDSPEGPEGEAPERRRKAHGMLKLYYGLSEGEAAGRPAGPDPLDP
  TDLNGAHFDPEVYLDKLRRECPLAQLMDSETDMVRQIRALDSDMQTLVYENYNKFISATD
  TIRKMKNDFRKMEDEMDRLATNMAVITDFSARISATLQDRHERITKLAGVHALLRKLQFL
  FELPSRLTKCVELGAYGQAVRYQGRAQAVLQQYQHLPSFRAIQDDCQVITARLAQQLRQR
  FREGGSGAPEQAECVELLLALGEPAEELCEEFLAHARGRLEKELRNLEAELGPSPPAPDV
  LEFTDHGGSGFVGGLCQVAAAYQELFAAQGPAGAEKLAAFARQLGSRYFALVERRLAQEQ
  GGGDNSLLVRALDRFHRRLRAPGALLAAAGLADAATEIVERVARERLGHHLQGLRAAFLG
  CLTDVRQALAAPRVAGKEGPGLAELLANVASSILSHIKASLAAVHLFTAKEVSFSNKPYF
  RGEFCSQGVREGLIVGFVHSMCQTAQSFCDSPGEKGGATPPALLLLLSRLCLDYETATIS
  YILTLTDEQFLVQDQFPVTPVSTLCAEARETARRLLTHYVKVQGLVISQMLRKSVETRDW
  LSTLEPRNVRAVMKRVVEDTTAIDVQVGLLYEEGVRKAQSSDSSKRTFSVYSSSRQQGRY
  APSYTPSAPMDTNLLSNIQKLFSERIDVFSPVEFNKVSVLTGIIKISLKTLLECVRLRTF
  GRFGLQQVQVDCHFLQLYLWRFVADEELVHLLLDEVVASAALRCPDPVPMEPSVVEVICE
  RG
• 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 protein retrieval from endosomes to the TGN, acid hydrolase sorting, lysosome function, endosomal cholesterol traffic and autophagy. VPS51 participates in retrograde transport of acid hydrolase receptors, likely by promoting tethering and SNARE-dependent fusion of endosome-derived carriers to the TGN. 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pontocerebellar hypoplasia, type 13	DISWPQUM	Moderate	Autosomal recessive	[1]

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 51 homolog.	[2]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Vacuolar protein sorting-associated protein 51 homolog.	[5]

3 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 51 homolog.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vacuolar protein sorting-associated protein 51 homolog.	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Vacuolar protein sorting-associated protein 51 homolog.	[6]

References

• [1] A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes. Hum Mol Genet. 2019 May 1;28(9):1548-1560. doi: 10.1093/hmg/ddy423.
• [2] 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.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [6] 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.