Neuraminidase
| 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 | ||||||||||
| SCOP2 | 2bat / SCOPe / SUPFAM | ||||||||||
| |||||||||||
| sialidase 1 (lysosomal sialidase) | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | NEU1 | ||||||
| NCBI gene | 4758 | ||||||
| HGNC | 7758 | ||||||
| OMIM | 608272 | ||||||
| RefSeq | NM_000434 | ||||||
| UniProt | Q99519 | ||||||
| Other data | |||||||
| Locus | Chr. 6 p21 | ||||||
| |||||||
| sialidase 2 (cytosolic sialidase) | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | NEU2 | ||||||
| NCBI gene | 4759 | ||||||
| HGNC | 7759 | ||||||
| OMIM | 605528 | ||||||
| RefSeq | NM_005383 | ||||||
| UniProt | Q9Y3R4 | ||||||
| Other data | |||||||
| Locus | Chr. 2 q37 | ||||||
| |||||||
| sialidase 3 (membrane sialidase) | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | NEU3 | ||||||
| NCBI gene | 10825 | ||||||
| HGNC | 7760 | ||||||
| OMIM | 604617 | ||||||
| RefSeq | NM_006656 | ||||||
| UniProt | Q9UQ49 | ||||||
| Other data | |||||||
| Locus | Chr. 11 q13.5 | ||||||
| |||||||
| sialidase 4 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | NEU4 | ||||||
| NCBI gene | 129807 | ||||||
| HGNC | 21328 | ||||||
| OMIM | 608527 | ||||||
| RefSeq | NM_080741 | ||||||
| UniProt | Q8WWR8 | ||||||
| Other data | |||||||
| Locus | Chr. 2 q37.3 | ||||||
| |||||||
Template:FixBunching Neuraminidase enzymes are glycoside hydrolase enzymes (EC 3.2.1.18) which cleave the glycosidic linkages of neuraminic acid. 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]
Enzymatic mechanism of influenza virus sialidase
The enzymatic mechanism of influenza virus sialidase has been studied by Taylor and coworkers, shown in Figure 1. The enzyme catalysis process includes 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.[5]
Subtypes
Swiss-Prot lists 137 types of neuraminidase from various species as of October 18, 2006.[6] 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].
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.
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.[7] 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.[8]
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.[9]
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.[10] A series of amide-linked C9 modified Neu5Ac2en have been reported by Megesh and colleagues as NEU1 inhibitors.[11]
See also
Neuraminidase Enzymes
- Viral neuraminidase
- Bacterial neuraminidase
- Mammalian neuraminidases
References
- ^ PDB: 1nna; Bossart-Whitaker P, Carson M, Babu YS, Smith CD, Laver WG, Air GM (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.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ von Itzstein M (2007). "The war against influenza: discovery and development of sialidase inhibitors". Nature Reviews. Drug Discovery. 6 (12): 967–74. doi:10.1038/nrd2400. PMID 18049471.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Palese P, Tobita K, Ueda M, Compans RW (1974). "Characterization of temperature sensitive influenza virus mutants defective in neuraminidase". Virology. 61 (2): 397–410. doi:10.1016/0042-6822(74)90276-1. PMID 4472498.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Liu C, Eichelberger MC, Compans RW, Air GM (1995). "Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding". Journal of Virology. 69 (2): 1099–106. PMC 188682. PMID 7815489.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Taylor NR, von Itzstein M (1994). "Molecular modeling studies on ligand binding to sialidase from influenza virus and the mechanism of catalysis". Journal of Medicinal Chemistry. 37 (5): 616–24. doi:10.1021/jm00031a011. PMID 8126701.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Search in UniProt Knowledgebase (Swiss-Prot and TrEMBL) for: neuraminidase
- ^ Drickamer, Kurt; Taylor, Maureen P. (2006). Introduction to glycobiology. Oxford [Oxfordshire]: Oxford University Press. pp. 177–178. ISBN 0-19-928278-1.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Dyason, Jeffrey C.; Itzstein, Mark von (2001), "Anti-Influenza Virus Drug Design: Sialidase Inhibitors", Australian Journal of Chemistry, 54 (11): 663–670, doi:10.1071/CH01173
- ^ Fgedi, Pťer (2006). The organic chemistry of sugars. Washington, DC: Taylor & Francis. pp. 822–823. ISBN 0-8247-5355-0.
- ^ von Itzstein M, Wu WY, Jin B (1994). "The synthesis of 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid: a potent influenza virus sialidase inhibitor". Carbohydrate Research. 259 (2): 301–5. doi:10.1016/0008-6215(94)84065-2. PMID 8050102.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Magesh S, Moriya S, Suzuki T, Miyagi T, Ishida H, Kiso M (2008). "Design, synthesis, and biological evaluation of human sialidase inhibitors. Part 1: selective inhibitors of lysosomal sialidase (NEU1)". Bioorganic & Medicinal Chemistry Letters. 18 (2): 532–7. doi:10.1016/j.bmcl.2007.11.084. PMID 18068975.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
External links
- Neuraminidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)