neuraminidase

Neuraminic acid

Neuraminidase
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	Neur
Pfam	PF00064
InterPro	IPR001860
SCOP	2bat
Available PDB structures: 1a14, 1a4g, 1a4q, 1b9s, 1b9t, 1b9v, 1inf, 1ing, 1inh, 1ivb, 1ivc, 1ivd, 1ive, 1ivf, 1ivg, 1l7f, 1l7g, 1l7h, 1nca, 1ncb, 1ncc, 1ncd, 1nmc, 1nna, 1nnb, 1nsb, 1nsc, 1nsd, 1v0z, 1vcj, 1w1x, 1w20, 1w21, 1xoe, 1xog, 2aeq, 2b8h, 2ht5, 2ht7

Neuraminidase enzymes are glycoside hydrolase enzymes (EC 3.2.1.18) which cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of influenza infection. The viral neuraminidases are frequently used as an antigenic determinants found on the surface of the Influenza virus. Some variants of the influenza neuraminidase confer more virulence to the virus than others. Other homologs are found in mammalian cells which have a range of functions. At least four mammalian sialidase homologs have been described in the human genome (see NEU1, NEU2, NEU3, NEU4).

Neuraminidases, also called sialidases, catalyze the hydrolysis of terminal sialic acid residues from the newly formed virions and from the host cell receptors.^[2] 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.^[3][4]

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^[5][6]
• Endo hydrolysis of (2→8)-α-sialosyl linkages in oligo- or poly(sialic) acids^[6]

Subtypes

Swiss-Prot lists 137 types of neuraminidase from various species as of October 18, 2006.^[7] 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 man, and strains with N3 or N7 subtypes have been identified in a number of isolated deaths.^{[citation needed]}

The following is a list of major classes of neuraminidase enzymes:

• Viral neuraminidase
• Bacterial neuraminidase
• Mammalian neuraminidases:

Structure

Influenza neuraminidase exists as a mushroom-shape 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.

Mechanism

The enzymatic mechanism of influenza virus sialidase has been studied by Taylor and coworkers, 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 conformer to a boat conformer when the sialoside binds to the sialidase. The second step leads to an oxocarbocation ion intermediate, the sialosyl cation. The third step is the formation and the last step affords α-Neu5Ac then it mutarotates to the more favourable anomer β-Neu5Ac.^[8]

Inhibitors

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.

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.^[9] 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.^[10]

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. To prepare structurally modified Neu5Ac2en derivatives may give more effective inhibitors.^[11]

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.^[12] A series of amide-linked C9 modified Neu5Ac2en have been reported by Megesh and colleagues as NEU1 inhibitors.^[13]

See also

• Glycoside hydrolase
• Neuraminidase inhibitors

References

External links

• MeSH Neuraminidase

• Orthomyxoviruses, Robert B. Couch, UTMB. Article includes a good clear line drawing of a neuraminidase on an influenza virus.