Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXL5W8F)

• DOT Name: Sorting nexin-3 (SNX3)
• Synonyms: Protein SDP3
• Gene Name: SNX3
• Related Disease:
  Alzheimer disease
  Autosomal dominant prognathism
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Isolated congenital microcephaly
  Parkinson disease
  Squamous cell carcinoma
  Microphthalmia
  Split hand-foot malformation
  Intellectual disability
  MMEP syndrome
• UniProt ID: SNX3_HUMAN
• PDB ID: 2MXC; 2YPS; 5F0J; 5F0L; 5F0M; 5F0P; 7BLO
• Pfam ID: PF00787
• Sequence:
  MAETVADTRRLITKPQNLNDAYGPPSNFLEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIF
  KLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKAFLRQLPFRGDDGIFDDNFIEERKQ
  GLEQFINKVAGHPLAQNERCLHMFLQDEIIDKSYTPSKIRHA
• Function: Phosphoinositide-binding protein required for multivesicular body formation. Specifically binds phosphatidylinositol 3-phosphate (PtdIns(P3)). Can also bind phosphatidylinositol 4-phosphate (PtdIns(P4)), phosphatidylinositol 5-phosphate (PtdIns(P5)) and phosphatidylinositol 3,5-biphosphate (PtdIns(3,5)P2). Plays a role in protein transport between cellular compartments. Together with RAB7A facilitates endosome membrane association of the retromer cargo-selective subcomplex (CSC/VPS). May in part act as component of the SNX3-retromer complex which mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. Promotes stability and cell surface expression of epithelial sodium channel (ENAC) subunits SCNN1A and SCNN1G. Not involved in EGFR degradation. Involved in the regulation of phagocytosis in dendritic cells possibly by regulating EEA1 recruitment to the nascent phagosomes. Involved in iron homeostasis through regulation of endocytic recycling of the transferrin receptor TFRC presumably by delivering the transferrin:transferrin receptor complex to recycling endosomes; the function may involve the CSC retromer subcomplex. In the case of Salmonella enterica infection plays arole in maturation of the Salmonella-containing vacuole (SCV) and promotes recruitment of LAMP1 to SCVs.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  Ub-specific processing proteases (R-HSA-5689880)
  WNT ligand biogenesis and trafficking (R-HSA-3238698)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Autosomal dominant prognathism	DIS2G3FF	Strong	Genetic Variation	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Strong	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[6]
Microphthalmia	DISGEBES	Disputed	Genetic Variation	[7]
Split hand-foot malformation	DIS8PKGD	Disputed	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Limited	Biomarker	[7]
MMEP syndrome	DIS78DLS	Limited	Autosomal dominant	[7]

6 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 Sorting nexin-3 (SNX3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sorting nexin-3 (SNX3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sorting nexin-3 (SNX3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sorting nexin-3 (SNX3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sorting nexin-3 (SNX3).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Sorting nexin-3 (SNX3).	[13]

References

• [1] Overexpression of SNX3 Decreases Amyloid- Peptide Production by Reducing Internalization of Amyloid Precursor Protein.Neurodegener Dis. 2018;18(1):26-37. doi: 10.1159/000486199. Epub 2018 Feb 7.
• [2] Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes.BMC Med Genet. 2007 Jul 26;8:48. doi: 10.1186/1471-2350-8-48.
• [3] Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia.J Cell Commun Signal. 2017 Jun;11(2):137-145. doi: 10.1007/s12079-016-0357-3. Epub 2016 Oct 24.
• [4] SNX3 suppresses the migration and invasion of colorectal cancer cells by reversing epithelial-to-mesenchymal transition via the -catenin pathway.Oncol Lett. 2019 Nov;18(5):5332-5340. doi: 10.3892/ol.2019.10860. Epub 2019 Sep 12.
• [5] Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of Parkinson's disease.Hum Mol Genet. 2018 May 1;27(9):1514-1532. doi: 10.1093/hmg/ddy059.
• [6] SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells.Cell Mol Life Sci. 2012 May;69(9):1505-21. doi: 10.1007/s00018-011-0887-z. Epub 2011 Dec 11.
• [7] Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype. J Med Genet. 2002 Dec;39(12):893-9. doi: 10.1136/jmg.39.12.893.
• [8] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.