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Neuraminidase (Sialidase) enzymes are
glycoside hydrolase 1HNY, a glycoside hydrolase Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalysis, catalyze the hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The ...
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
s that cleave (cut) the
glycosidic linkage A glycosidic bond or glycosidic linkage is a type of covalent bond A covalent bond is a chemical bond that involves the sharing of electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs, and the stable ba ...
s of
neuraminic acid Neuraminic acid (5-amino-3,5-dideoxy-D-''glycero''-D-''galacto''-non-2-ulosonic acid) is an acidic (in particular ulusonic) amino sugar with a backbone formed by nine carbon atoms. Although 9-carbon sugars do not occur naturally, neuraminic ...
s. Neuraminidase enzymes are a large family, found in a range of organisms. The best-known neuraminidase is the
viral neuraminidase Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid (also called neuraminic acid) groups from ...
, a drug target for the prevention of the spread of
influenza Influenza, commonly known as "the flu", is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), ...

influenza
infection. The viral neuraminidases are frequently used as antigenic determinants found on the surface of the influenza virus. Some variants of the influenza neuraminidase confer more
virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most contexts, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host (biology), host. The Pathogen#Pathogenicity, ...
to the virus than others. Other homologues are found in mammalian cells, which have a range of functions. At least four mammalian
sialidase Neuraminidase (Sialidase) enzymes are glycoside hydrolase enzymes that cleave (cut) the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The best-known neuraminidase is the viral neu ...
homologues have been described in the
human genome The human genome is a complete set of nucleic acid sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides Nucleotides are organic molecules c ...

human genome
(see
NEU1
NEU1
,
NEU2
NEU2
,
NEU3
NEU3
,
NEU4 Sialidase-4 is an enzyme Enzymes () are s that act as s (biocatalysts). Catalysts accelerate . The molecules upon which enzymes may act are called , and the enzyme converts the substrates into different molecules known as . Almost all in t ...

NEU4
). Sialidases may act as pathogenic factors in microbial infections.


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 * Endo hydrolysis of (2→8)-α-sialosyl linkages in oligo- or poly(sialic) acids


Function

Neuraminidases, also called sialidases, catalyze the hydrolysis of terminal
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 Sweden, Swedish biochemist Gunnar Blix in 1952. The most common member of ...

sialic acid
residues from the newly formed
virions A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous syst ...

virions
and from the host cell receptors. Sialidase activities include assistance in the mobility of virus particles through the respiratory tract mucus and in the elution of virion progeny from the infected cell.


Subtypes

Swiss-Prot lists 137 types of neuraminidase from various species as of October 18, 2006. Nine subtypes of influenza neuraminidase are known; many occur only in various species of duck and chicken. Subtypes N1 and N2 have been positively linked to epidemics in humans, and strains with N3 or N7 subtypes have been identified in a number of isolated deaths.
CAZy CAZy is a database of Carbohydrate-Active enZYmes (CAZymes). The database contains a classification and associated information about enzymes involved in the synthesis, metabolism, and recognition of complex carbohydrates, i.e. disaccharides, oligo ...
defines a total of 85 glycosyl hydrolase families, of which families GH34 (viral), GH33 (cellular organisms), GH58 (viral and bacterial), GH83 (viral) are major families that contain this enzyme. GH58 is the only endo-acting family. The following is a list of major classes of neuraminidase enzymes: *
Viral neuraminidase Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid (also called neuraminic acid) groups from ...
* Bacterial neuraminidase * Mammalian neuraminidases:


Structure

Influenza Influenza, commonly known as "the flu", is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), ...

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 In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, mechan ...
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. The structure of trans-sialidase includes a catalytic
beta-propeller In structural biology, a beta-propeller (β-propeller) is a type of all-β protein fold, all-β protein architecture characterized by 4 to 8 highly symmetrical blade-shaped beta sheets arranged toroidally around a central axis. Together the beta-sh ...
domain, a N-terminal
lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar Moiety (chemistry), groups that are part of other molecules, so cause agglutination (biology), agglutination of particular cells or precipitation of Glycoconjugate, gly ...
-like domain and an irregular beta-stranded domain inserted into the catalytic domain. Recent emergence of
oseltamivir Oseltamivir, sold under the brand name Tamiflu, is an antiviral drug, antiviral medication used to treat and prevent influenza A virus, influenza A and Influenza B virus, influenza B (flu). Many medical organizations recommend it in people who h ...

oseltamivir
and
zanamivir Zanamivir is a medication used to treat and prevent influenza Influenza, commonly called "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, mus ...

zanamivir
resistant
human influenza Influenza, commonly called "the flu", is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host ...
A(
H1N1 In virology Virology is the scientific study of virusessubmicroscopic, parasitic organisms of genetic material contained in a protein coatand virus-like agents. It focuses on the following aspects of viruses: their structure, classificatio ...
) H274Y has emphasized the need for suitable expression systems to obtain large quantities of highly pure and stable,
recombinantRecombinant may refer to: * Recombinant organism A genetically modified organism (GMO) is any organism whose genetic material has been altered using genetic engineering techniques. The exact definition of a genetically modified organism and wha ...
neuraminidase through two separate artificial tetramerization domains that facilitate the formation of catalytically active neuraminidase homotetramers from
yeast Yeasts are eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular ...

yeast
and
Staphylothermus In taxonomy, ''Staphylothermus'' is a genus of the Desulfurococcaceae. Taxonomy Desulfurococcaceae are anaerobic organism, anaerobic, sulfur respiring, extreme thermophiles. Desulfurococcaceae share the same family as Desulfurococcus. Two spec ...
marinus, which allow for secretion of
FLAG-tagFLAG-tag, or FLAG octapeptide, or FLAG epitope, is a polypeptide protein tag that can be added to a protein using recombinant DNA Image:recombinant formation of plasmids.svg, 280px, Construction of recombinant DNA, in which a foreign DNA fragment is ...
ged
proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

proteins
and further purification.


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.


Inhibitors

Neuraminidase inhibitorNeuraminidase inhibitors (NAIs) are a class of drug File:Aspirine macro shot.jpg, Uncoated aspirin Tablet (pharmacy), tablets, consisting of about 90% acetylsalicylic acid, along with a minor amount of inert fillers and binders. Aspirin is a phar ...
s are useful for combating
influenza Influenza, commonly known as "the flu", is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), ...

influenza
infection:
zanamivir Zanamivir is a medication used to treat and prevent influenza Influenza, commonly called "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, mus ...

zanamivir
, administered by inhalation;
oseltamivir Oseltamivir, sold under the brand name Tamiflu, is an antiviral drug, antiviral medication used to treat and prevent influenza A virus, influenza A and Influenza B virus, influenza B (flu). Many medical organizations recommend it in people who h ...

oseltamivir
, administered orally;
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, transition-state analogue inhibitor of influenza viral ...

peramivir
administered parenterally, that is through intravenous or intramuscular injection; and which is in phase III clinical trials. 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. 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. The unsaturated sialic acid (N-acetylneuraminic acid eu5ac 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. 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. A series of amide-linked C9 modified Neu5Ac2en have been reported by Megesh and colleagues as NEU1 inhibitors.


See also

* Glycoside hydrolase family 33 *
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 ...
*
Hemagglutinin (influenza) Influenza hemagglutinin (HA) or haemagglutinin .html" ;"title="/sup>">/sup> (British English British English (BrE) is the standard dialect of the English language English is a West Germanic languages, West Germanic language first s ...


References


External links

*
Orthomyxoviruses
Robert B. Couch, UTMB. Article includes a good clear line drawing of a neuraminidase on an influenza virus. {{Authority control Carbohydrate chemistry EC 3.2.1 Glycobiology Neuraminidase inhibitors