Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ5PQOW)

• DOT Name: Sialidase-3 (NEU3)
• Synonyms: EC 3.2.1.18; Ganglioside sialidasedis; Membrane sialidase; N-acetyl-alpha-neuraminidase 3
• Gene Name: NEU3
• Related Disease:
  Nervous system disease
  Acute lymphocytic leukaemia
  Adult glioblastoma
  Advanced cancer
  Carcinoma
  Childhood acute lymphoblastic leukemia
  Colon carcinoma
  Colonic neoplasm
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Melanoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pulmonary fibrosis
  Renal cell carcinoma
  Rheumatoid arthritis
  Colon cancer
  Tay-sachs disease
  Clear cell adenocarcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: NEUR3_HUMAN
• EC Number: 3.2.1.18
• Pfam ID: PF13088
• Sequence:
  MEEVTTCSFNSPLFRQEDDRGITYRIPALLYIPPTHTFLAFAEKRSTRRDEDALHLVLRR
  GLRIGQLVQWGPLKPLMEATLPGHRTMNPCPVWEQKSGCVFLFFICVRGHVTERQQIVSG
  RNAARLCFIYSQDAGCSWSEVRDLTEEVIGSELKHWATFAVGPGHGIQLQSGRLVIPAYT
  YYIPSWFFCFQLPCKTRPHSLMIYSDDLGVTWHHGRLIRPMVTVECEVAEVTGRAGHPVL
  YCSARTPNRCRAEALSTDHGEGFQRLALSRQLCEPPHGCQGSVVSFRPLEIPHRCQDSSS
  KDAPTIQQSSPGSSLRLEEEAGTPSESWLLYSHPTSRKQRVDLGIYLNQTPLEAACWSRP
  WILHCGPCGYSDLAALEEEGLFGCLFECGTKQECEQIAFRLFTHREILSHLQGDCTSPGR
  NPSQFKSN
• Function: Exo-alpha-sialidase that catalyzes the hydrolytic cleavage of the terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) of a glycan moiety in the catabolism of glycolipids, glycoproteins and oligosacharides. Displays high catalytic efficiency for gangliosides including alpha-(2->3)-sialylated GD1a and GM3 and alpha-(2->8)-sialylated GD3. Plays a role in the regulation of transmembrane signaling through the modulation of ganglioside content of the lipid bilayer and by direct interaction with signaling receptors, such as EGFR. Desialylates EGFR and activates downstream signaling in proliferating cells. Contributes to clathrin-mediated endocytosis by regulating sorting of endocytosed receptors to early and recycling endosomes.
• Tissue Specificity: Highly expressed in skeletal muscle, testis, adrenal gland and thymus, followed by pancreas, liver, heart and thymus. Weakly expressed in kidney, placenta, brain and lung.
• KEGG Pathway:
  Other glycan degradation (hsa00511)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Glycosphingolipid catabolism (R-HSA-9840310)
  Sialic acid metabolism (R-HSA-4085001)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Melanoma	DIS1RRCY	Strong	Altered Expression	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[6]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[10]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[11]
Colon cancer	DISVC52G	moderate	Altered Expression	[7]
Tay-sachs disease	DISWG5B4	moderate	Biomarker	[12]
Clear cell adenocarcinoma	DISYUGHZ	Limited	Altered Expression	[13]
Prostate cancer	DISF190Y	Limited	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sialidase-3 (NEU3).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sialidase-3 (NEU3).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sialidase-3 (NEU3).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sialidase-3 (NEU3).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sialidase-3 (NEU3).	[19]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Sialidase-3 (NEU3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sialidase-3 (NEU3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sialidase-3 (NEU3).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sialidase-3 (NEU3).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sialidase-3 (NEU3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sialidase-3 (NEU3).	[26]
Catechol	DML0YEK	Investigative	Catechol increases the expression of Sialidase-3 (NEU3).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sialidase-3 (NEU3).	[25]

References

• [1] Presence of aberrant epididymal tubules revealing undifferentiated epithelial cells and absence of spermatozoa in a combined neuraminidase-3 and -4 deficient adult mouse model.PLoS One. 2018 Oct 25;13(10):e0206173. doi: 10.1371/journal.pone.0206173. eCollection 2018.
• [2] Down regulation of membrane-bound Neu3 constitutes a new potential marker for childhood acute lymphoblastic leukemia and induces apoptosis suppression of neoplastic cells.Int J Cancer. 2010 Jan 15;126(2):337-49. doi: 10.1002/ijc.24733.
• [3] Overexpression of sialidase NEU3 increases the cellular radioresistance potential of U87MG glioblastoma cells.Biochem Biophys Res Commun. 2019 Jan 1;508(1):31-36. doi: 10.1016/j.bbrc.2018.11.086. Epub 2018 Nov 20.
• [4] Roles of plasma membrane-associated sialidase NEU3 in human cancers.Biochim Biophys Acta. 2008 Mar;1780(3):532-7. doi: 10.1016/j.bbagen.2007.09.016. Epub 2007 Oct 2.
• [5] Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression.Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10718-23. doi: 10.1073/pnas.152597199. Epub 2002 Jul 29.
• [6] Deregulation of sialidases in human normal and tumor tissues.Cancer Biomark. 2018 Feb 14;21(3):591-601. doi: 10.3233/CBM-170548.
• [7] Membrane sialidase NEU3 is highly expressed in human melanoma cells promoting cell growth with minimal changes in the composition of gangliosides.Cancer Sci. 2011 Dec;102(12):2139-49. doi: 10.1111/j.1349-7006.2011.02086.x. Epub 2011 Oct 17.
• [8] Non-small cell lung cancer (NSCLC), EGFR downstream pathway activation and TKI targeted therapies sensitivity: Effect of the plasma membrane-associated NEU3.PLoS One. 2017 Oct 31;12(10):e0187289. doi: 10.1371/journal.pone.0187289. eCollection 2017.
• [9] Attenuated pulmonary fibrosis in sialidase-3 knockout (Neu3(-/-)) mice.Am J Physiol Lung Cell Mol Physiol. 2020 Jan 1;318(1):L165-L179. doi: 10.1152/ajplung.00275.2019. Epub 2019 Oct 16.
• [10] The plasma membrane sialidase NEU3 regulates the malignancy of renal carcinoma cells by controlling 1 integrin internalization and recycling.J Biol Chem. 2012 Dec 14;287(51):42835-45. doi: 10.1074/jbc.M112.407718. Epub 2012 Nov 8.
• [11] -2,3-Sialyltransferase 1 and neuraminidase-3 from monocytes in patients with rheumatoid arthritis correlate with disease activity measures: A pilot study.J Chin Med Assoc. 2019 Mar;82(3):179-185. doi: 10.1097/JCMA.0000000000000027.
• [12] Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease.Exp Neurol. 2018 Jan;299(Pt A):26-41. doi: 10.1016/j.expneurol.2017.09.012. Epub 2017 Sep 30.
• [13] Expression of NEU3 (plasma membrane-associated sialidase) in clear cell adenocarcinoma of the ovary: its relationship with T factor of pTNM classification.Oncol Res. 2006;16(6):289-97. doi: 10.3727/000000006783981035.
• [14] Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling.Cell Death Differ. 2012 Jan;19(1):170-9. doi: 10.1038/cdd.2011.83. Epub 2011 Jun 17.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] 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.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4578-83.
• [20] Phenolic metabolites of benzene induced caspase-dependent cytotoxicities to K562 cells accompanied with decrease in cell surface sialic acids. Environ Toxicol. 2014 Dec;29(12):1437-51. doi: 10.1002/tox.21874. Epub 2013 Jun 17.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] 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.
• [26] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.