Details of Drug Off-Target (DOT)

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

• DOT Name: Cation-dependent mannose-6-phosphate receptor (M6PR)
• Synonyms: CD Man-6-P receptor; CD-MPR; 46 kDa mannose 6-phosphate receptor; MPR 46
• Gene Name: M6PR
• UniProt ID: MPRD_HUMAN
• PDB ID: 1JUQ
• Pfam ID: PF02157
• Sequence:
  MFPFYSCWRTGLLLLLLAVAVRESWQTEEKTCDLVGEKGKESEKELALVKRLKPLFNKSF
  ESTVGQGSDTYIYIFRVCREAGNHTSGAGLVQINKSNGKETVVGRLNETHIFNGSNWIML
  IYKGGDEYDNHCGKEQRRAVVMISCNRHTLADNFNPVSEERGKVQDCFYLFEMDSSLACS
  PEISHLSVGSILLVTFASLVAVYVVGGFLYQRLVVGAKGMEQFPHLAFWQDLGNLVADGC
  DFVCRSKPRNVPAAYRGVGDDQLGEESEERDDHLLPM
• Function: Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex.
• KEGG Pathway:
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Glycosphingolipid catabolism (R-HSA-9840310)
  Lysosome Vesicle Biogenesis (R-HSA-432720)

Molecular Interaction Atlas (MIA) of This DOT

13 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 Cation-dependent mannose-6-phosphate receptor (M6PR).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[13]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Cation-dependent mannose-6-phosphate receptor (M6PR).	[15]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine affects the localization of Cation-dependent mannose-6-phosphate receptor (M6PR).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cation-dependent mannose-6-phosphate receptor (M6PR).	[14]

References

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• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [9] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [10] Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435-1455. doi: 10.1080/15548627.2018.1474314. Epub 2018 Jul 20.
• [11] 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.
• [12] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [13] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [14] 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.
• [15] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.