Viral neuraminidase is a type of

neuraminidase Exo-α-sialidase (EC 3.2.1.18, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids: : Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glycos ...

found on the surface of

influenza virus ''Orthomyxoviridae'' (from Greek ὀρθός, ''orthós'' 'straight' + μύξα, ''mýxa'' 'mucus') is a family of negative-sense RNA viruses. It includes seven genera: ''Alphainfluenzavirus'', ''Betainfluenzavirus'', '' Gammainfluenzavirus'', ...

es that enables the virus to be released from the host cell. Neuraminidases are

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s that cleave

sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this gr ...

(also called

neuraminic acid Neuraminic acid (5-amino-3,5-dideoxy-D-''glycero''-D-''galacto''-non-2-ulosonic acid) is an acidic (in particular ulosonic) amino sugar with a backbone formed by nine carbon atoms. Although 9-carbon sugars do not occur naturally, neuraminic ...

) groups from

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

Neuraminidase inhibitors Neuraminidase inhibitors (NAIs) are a class of drugs which block the neuraminidase enzyme. They are a commonly used antiviral drug type against influenza. Viral neuraminidases are essential for influenza reproduction, facilitating viral budding from ...

are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza. Viral neuraminidases are the members of the glycoside hydrolase family 3
CAZY GH_34
which comprises enzymes with only one known activity;

sialidase Exo-α-sialidase (EC 3.2.1.18, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids: : Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glycos ...

. Neuraminidases cleave the terminal

residues from carbohydrate chains in glycoproteins. Sialic acid is a negatively charged sugar associated with the protein and lipid portions of

lipoproteins A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...

. To infect a host cell, the influenza virus attaches to the exterior cell surface using

hemagglutinin In molecular biology, hemagglutinins (or ''haemagglutinin'' in British English) (from the Greek , 'blood' + Latin , 'glue') are receptor-binding membrane fusion glycoproteins produced by viruses in the ''Paramyxoviridae'' family. Hemagglutinins ar ...

, a molecule found on the surface of the virus that binds to sialic acid groups. Sialic acids are found on various

s at the host cell surface. The virus then moves from sialic acid group to sialic acid group until it finds the proper cell surface receptor (whose identity remains unknown). Neuraminadase enables this movement by cleaving sialic acid groups that hemagglutinin was attached to. After the virus has entered the cell and has replicated, new viral particles bud from the host cell membrane. The hemagglutinin on new viral particles remains attached to sialic acid groups of glycoproteins on the external cell surface and the surface of other viral particles; neuraminadase cleaves these groups and thereby allows the release of viral particles and prevents self-aggregation. Neuraminadase also facilitates the movement of virus particles in the presence of mucus rich in silicic acid. A single

hemagglutinin-neuraminidase Hemagglutinin-neuraminidase refers to a single viral protein that has both hemagglutinin and (endo) neuraminidase activity. This is in contrast to the proteins found in influenza, where both functions exist but in two separate proteins. Its neura ...

protein can combine neuraminidase and

functions, such as in

mumps virus The mumps virus (MuV) is the virus that causes mumps. MuV contains a single-stranded, negative-sense genome made of ribonucleic acid (RNA). Its genome is about 15,000 nucleotides in length and contains seven genes that encode nine proteins. The g ...

and

human parainfluenza virus Human parainfluenza viruses (HPIVs) are the viruses that cause human parainfluenza. HPIVs are a paraphyletic group of four distinct single-stranded RNA viruses belonging to the ''Paramyxoviridae'' family. These viruses are closely associated wit ...

Function

The enzyme helps viruses to be released after budding from the plasma membrane of a host cell. Influenza virus membranes contain two

s: hemagglutinin and neuraminidase. While the

on the surface of the virion is needed for infection, its presence inhibits release of the particle after budding. Viral neuraminidase cleaves terminal

residues from

glycan The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate p ...

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.

Inhibitors

Neuraminidase has been targeted in structure-based enzyme inhibitor design programmes that have resulted in the production of two drugs,

zanamivir Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and ap ...

(Relenza) and

oseltamivir Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at hig ...

(Tamiflu). Administration of

neuraminidase inhibitor Neuraminidase inhibitors (NAIs) are a class of drugs which block the neuraminidase enzyme. They are a commonly used antiviral drug type against influenza. Viral neuraminidases are essential for influenza reproduction, facilitating viral budding from ...

s is a treatment that limits the severity and spread of viral infections. Neuraminidase inhibitors are useful for combating

influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...

infection:

, administered by inhalation;

, administered orally; and under research is

peramivir Peramivir (trade name Rapivab) is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and th ...

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 A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus which can cause illness in humans and many other animal species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of typ ...

influenza virus strain that was resistant to the drug

. 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 Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at hig ...

medication. The cause was determined to be a

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...

-to-

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

(

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

) substitution at position 274 in its neuraminidase protein. As strains of influenza are continuously mutating, it is essential that scientists quickly and efficiently determine the correct neuraminidase subtype that is responsible for the

drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...

in order to develop medications that will combat specific strains of influenza. A new class of neuraminidase inhibitors that covalently attach to the enzyme have shown activity against drug-resistant virus ''in vitro''.

Specificity

In ideal circumstances, influenza virus neuraminidase (NA) should act on the same type of receptor the virus

(HA) binds to, a phenomenon that 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 Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalyze the hydrolysis of glycosidic bonds in complex sugars. They are extremely common enzymes with roles in nature including degradation of biomass such as cellulose (cel ...

activity, and are classified as EC 3.2.1.29 (endo-neuraminidase) and EC 3.2.1.18 (exo-neuraminidases). In general, mammalian

residues are at terminal positions (non-reducing end) in complex glycans, and so viral neuraminidases - which are exo-

enzymes - use these terminal residues as their substrates.

References

External links

Influenza Research Database
Database of influenza sequences (including neuraminidase). * {{DEFAULTSORT:Viral Neuraminidase Viral enzymes Influenza A virus EC 3.2.1 GH family Protein families