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Viral neuraminidase: Wikis

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Hemagglutinin-neuraminidase
Neuraminidase Ribbon Diagram.jpg
Crystallographic structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid.[1]
Identifiers
Symbol HN
Pfam PF00423
InterPro IPR000665
SCOP 1usr
"NA" = neuraminidase
Influenza virus replication.

Viral neuraminidase is an enzyme on the surface of influenza viruses that enables the virus to be released from the host cell. Drugs that inhibit neuraminidase, known as neuraminidase inhibitors, are used to treat influenza.

When influenza virus reproduces, it attaches to the cell surface using hemagglutinin, a molecule found on the surface of the virus which binds to sialic acid groups. Sialic acids are found on various glycoproteins at the host cell surface, and the virus exploits these groups to bind the host cell. In order for the virus to be released from the cell, neuraminidase must enzymatically cleave the sialic acid groups from host glycoproteins.[2]

In some viruses, a hemagglutinin-neuraminidase protein combines the neuraminidase and hemagglutinin functions in a single protein.

Contents

Function

The enzyme helps viruses to be released from a host cell. Influenza virus membranes contain two glycoproteins: hemagglutinin and neuraminidase. While the hemagglutinin on the surface of the virion is needed for infection, its presence inhibits release of the particle after budding. Viral neuraminidase cleaves terminal neuraminic acid (also called sialic acid) residues from glycan structures on the surface of the infected cell. This promotes the release of progeny viruses and the spread of the virus from the host cell to uninfected surrounding cells. Neuraminidase also cleaves sialic acid residues from viral proteins, preventing aggregation of viruses.

Neuraminidase inhibitors

Neuraminidase has been targeted in structure-based enzyme inhibitor design programmes that have resulted in the production of two drugs, zanamivir (Relenza) and oseltamivir (Tamiflu). Administration of neuraminidase inhibitors is a treatment that limits the severity and spread of viral infections. Neuraminidase inhibitors are useful for combating influenza infection: zanamivir, administered by inhalation; oseltamivir, administered orally; and under research is peramivir administered parenterally, that is through intravenous or intramuscular injection.

Neuraminidase inhibition resistance

On February 27, 2005, a 14-year-old Vietnamese girl was documented to be carrying an H5N1 influenza virus strain that was resistant to the drug oseltamivir. The drug is used to treat patients that have contracted influenza. However, the Vietnamese girl who had received a prophylactic dose (75 mg once a day) was found to be non-responsive to the medication. In growing fears of a global avian flu pandemic, scientists began to look for a cause of resistance to the Tamiflu medication. The cause was determined to be a histidine-to-tyrosine (amino acid) substitution at position 274 in its neuraminidase protein.

As strains of influenza are continually mutating, it is essential that scientists quickly and efficiently determine the correct neuraminidase subtype that is responsible for the drug resistance in order to develop medications that will combat specific strains of influenza.

Specificity

Ideally, influenza virus neuraminidase (NA) should act on the same type of receptor the virus hemagglutinin (HA) binds to, a phenomenon which does not always happen. It is not quite clear how the virus manages to function when there is no close match between the specificities of NA and HA.

Exo- and endo-

Neuraminidase enzymes can have endo- or exo-glycosidase activity, and are classified as EC 3.2.1.29 (endo-neuraminidase)[3] and EC 3.2.1.18 (exo-neuraminidases)[4]. In general, mammalian sialic acid residues are at terminal positions (non-reducing end) in complex glycans, and so viral neuraminidases which are exo-glycosidase enzymes use these terminal residues as their substrates.

See also

References

  1. ^ PDB 1nna; Bossart-Whitaker P, Carson M, Babu YS, Smith CD, Laver WG, Air GM (August 1993). "Three-dimensional structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid". J. Mol. Biol. 232 (4): 1069–83. doi:10.1006/jmbi.1993.1461. PMID 8371267.  
  2. ^ Huang IC, Li W, Sui J, Marasco W, Choe H, Farzan M (May 2008). "Influenza A virus neuraminidase limits viral superinfection". J. Virol. 82 (10): 4834–43. doi:10.1128/JVI.00079-08. PMID 18321971. PMC 2346733. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=18321971.  
  3. ^ "EC 3.2.1.129". http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/2/1/129.html.  
  4. ^ "EC 3.2.1.18". http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/2/1/18.html.  

External links

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