Neuraminidase
exo-α-sialidase | |||||||||
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Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Exo-α-sialidase (
- Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glycosidic linkages of terminal sialic acid residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates
Neuraminidase enzymes are a large family, found in a range of organisms. The best-known neuraminidase is the
Reaction
There are two major classes of Neuraminidase that cleave exo or endo poly-sialic acids:
- Exo hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)-glycosidic linkages of terminal sialic acid residues[3][4]
- Endo hydrolysis of (2→8)-α-sialosyl linkages in oligo- or poly(sialic) acids[4] (see EC 3.2.1.129 endo-α-sialidase.)
Function
Sialidases, also called neuraminidases, catalyze the hydrolysis of terminal
Subtypes
The following is a list of major classes of neuraminidase enzymes:[citation needed]
- Viral neuraminidase
- Bacterial neuraminidase
- Mammalian neuraminidases:
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Structure
Influenza neuraminidase is a mushroom-shaped projection on the surface of the influenza virus. It has a head consisting of four co-planar and roughly spherical subunits, and a hydrophobic region that is embedded within the interior of the virus' membrane. It comprises a single polypeptide chain that is oriented in the opposite direction to the hemagglutinin antigen. The composition of the polypeptide is a single chain of six conserved polar amino acids, followed by hydrophilic, variable amino acids. β-Sheets predominate as the secondary level of protein conformation.[citation needed]
The structure of trans-sialidase includes a catalytic β-propeller domain, a N-terminal lectin-like domain and an irregular beta-stranded domain inserted into the catalytic domain.[10]
Recent emergence of
Mechanism
The enzymatic mechanism of influenza virus sialidase has been studied by Taylor et al., shown in Figure 1. The enzyme catalysis process has four steps. The first step involves the distortion of the α-sialoside from a 2C5 chair conformation (the lowest-energy form in solution) to a pseudoboat conformation when the sialoside binds to the sialidase. The second step leads to an oxocarbocation intermediate, the sialosyl cation. The third step is the formation of Neu5Ac initially as the α-anomer, and then mutarotation and release as the more thermodynamically stable β-Neu5Ac.[12]
Inhibitors
Neuraminidase inhibitors are useful for combating influenza infection: zanamivir, administered by inhalation; oseltamivir, administered orally; peramivir administered parenterally, that is through intravenous or intramuscular injection; and laninamivir which is in phase III clinical trials.[citation needed]
There are two major proteins on the surface of influenza virus particles. One is the lectin haemagglutinin protein with three relatively shallow sialic acid-binding sites and the other is enzyme sialidase with the active site in a pocket. Because of the relative deep active site in which low-molecular-weight inhibitors can make multiple favorable interactions and approachable methods of designing transition-state analogues in the hydrolysis of sialosides, the sialidase becomes more attractive anti-influenza drug target than the haemagglutinin.[13] After the X-ray crystal structures of several influenza virus sialidases were available, the structure-based inhibitor design was applied to discover potent inhibitors of this enzyme.[14]
The unsaturated sialic acid (N-acetylneuraminic acid [Neu5ac]) derivative 2-deoxy-2, 3-didehydro-D-N-acetylneuraminic acid (Neu5Ac2en), a sialosyl cation transition-state (Figure 2) analogue, is believed the most potent inhibitor core template. Structurally modified Neu5Ac2en derivatives may give more effective inhibitors.[15]
Many Neu5Ac2en-based compounds have been synthesized and tested for their influenza virus sialidase inhibitory potential. For example: The 4-substituted Neu5Ac2en derivatives (Figure 3), 4-amino-Neu5Ac2en (Compound 1), which showed two orders of magnitude better inhibition of influenza virus sialidase than Neu5Ac2en5 and 4-guanidino-Neu5Ac2en (Compound 2), known as Zanamivir, which is now marketed for treatment of influenza virus as a drug, have been designed by von Itzstein and coworkers.[16] A series of amide-linked C9 modified Neu5Ac2en have been reported by Megesh and colleagues as NEU1 inhibitors.[17]
See also
- Glycoside hydrolase family 33
- Neuraminidase inhibitors
- Hemagglutinin (influenza)
References
- ^ "WEHI History: 1957 Discovery of Neuraminidase - Key Flu Molecule". WEHI. Retrieved 2023-11-08.
- S2CID 21308462.
- PMID 6762816.
- ^ PMID 1883340.
- S2CID 36867756.
- PMID 4472498.
- PMID 7815489.
- ^ Search in UniProt Knowledgebase (Swiss-Prot and TrEMBL) for: neuraminidase[permanent dead link]
- ^ "CAZy search: activity: neuraminidase". www.cazy.org. Retrieved 28 April 2019.
- PMID 9562562.
- PMID 21326879.
- PMID 8126701.
- ISBN 0-19-928278-1.
- doi:10.1071/CH01173.
- ISBN 0-8247-5355-0.
- PMID 8050102.
- PMID 18068975.
External links
- Neuraminidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Orthomyxoviruses, Robert B. Couch, UTMB. Article includes a good clear line drawing of a neuraminidase on an influenza virus.