Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW76T35)

• DOT Name: Sialidase-2 (NEU2)
• Synonyms: EC 3.2.1.18; Cytosolic sialidase; N-acetyl-alpha-neuraminidase 2
• Gene Name: NEU2
• Related Disease:
  Allergic rhinitis
  Gastric cancer
  Stomach cancer
  Prostate cancer
  Prostate carcinoma
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: NEUR2_HUMAN
• PDB ID: 1SNT; 1SO7; 1VCU; 2F0Z; 2F10; 2F11; 2F12; 2F13; 2F24; 2F25; 2F26; 2F27; 2F28; 2F29; 4NC5; 4NCS
• EC Number: 3.2.1.18
• Pfam ID: PF13088
• Sequence:
  MASLPVLQKESVFQSGAHAYRIPALLYLPGQQSLLAFAEQRASKKDEHAELIVLRRGDYD
  APTHQVQWQAQEVVAQARLDGHRSMNPCPLYDAQTGTLFLFFIAIPGQVTEQQQLQTRAN
  VTRLCQVTSTDHGRTWSSPRDLTDAAIGPAYREWSTFAVGPGHCLQLHDRARSLVVPAYA
  YRKLHPIQRPIPSAFCFLSHDHGRTWARGHFVAQDTLECQVAEVETGEQRVVTLNARSHL
  RARVQAQSTNDGLDFQESQLVKKLVEPPPQGCQGSVISFPSPRSGPGSPAQWLLYTHPTH
  SWQRADLGAYLNPRPPAPEAWSEPVLLAKGSCAYSDLQSMGTGPDGSPLFGCLYEANDYE
  EIVFLMFTLKQAFPAEYLPQ
• 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. Recognizes sialyl linkage positions of the glycan moiety as well as the supramolecular organization of the sialoglycoconjugate. Displays preference for alpha-(2->3)-sialylated GD1a and GT1B gangliosides over alpha-(2->8)-sialylated GD1b, in both monomeric forms and micelles. Hydrolyzes monomeric GM1 ganglioside, but has no activity toward the miscellar form. Has lower sialidase activity for glycoproteins such as fetuin and TF/transferrin that carry a mixture of alpha-(2->3) and alpha-(2->6)-sialyl linkages. Cleaves milk oligosaccharide alpha-(2->3)-sialyllactose, but is inactive toward alpha-(2->6)-sialyllactose isomer. Has no activity toward colominic acid, a homomer of alpha-(2->8)-linked Neu5Ac residues.
• Tissue Specificity: Expressed in skeletal muscle, fetal liver and embryonic carcinoma cell line NT2-D1.
• 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Prostate cancer	DISF190Y	moderate	Altered Expression	[3]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[3]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[4]
Pancreatic cancer	DISJC981	Limited	Biomarker	[4]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[4]

1 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 Sialidase-2 (NEU2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sialidase-2 (NEU2).	[6]

References

• [1] Individualized Treatment of Allergic Rhinitis According to Nasal Cytology.Allergy Asthma Immunol Res. 2017 Sep;9(5):403-409. doi: 10.4168/aair.2017.9.5.403.
• [2] Co-Expression of NEU2 and GBA3 Causes a Drastic Reduction in Cytosolic Sialyl Free N-glycans in Human MKN45 Stomach Cancer Cells-Evidence for the Physical Interaction of NEU2 and GBA3.Biomolecules. 2015 Jul 16;5(3):1499-514. doi: 10.3390/biom5031499.
• [3] Human cytosolic sialidase NEU2-low general tissue expression but involvement in PC-3 prostate cancer cell survival.Biochem Biophys Res Commun. 2012 Nov 9;428(1):142-9. doi: 10.1016/j.bbrc.2012.10.028. Epub 2012 Oct 12.
• [4] Association of cytosolic sialidase Neu2 with plasma membrane enhances Fas-mediated apoptosis by impairing PI3K-Akt/mTOR-mediated pathway in pancreatic cancer cells.Cell Death Dis. 2018 Feb 12;9(2):210. doi: 10.1038/s41419-017-0191-4.
• [5] 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.
• [6] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.