neuraminidase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/03 06:39:18」(JST)

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Neuraminidase diagram

N-Acetylneuraminic acid

Neuraminidase enzymes are glycoside hydrolase enzymes (EC 3.2.1.18) that cleave 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 neuraminidase, a drug target for the prevention of the spread of 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 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).

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

exo-α-sialidase Identifiers EC number 3.2.1.18 CAS number 9001-67-6 Databases IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures RCSB PDB PDBe PDBsum Gene Ontology AmiGO / EGO Search PMC articles PubMed articles NCBI proteins

endo-α-sialidase Identifiers EC number 3.2.1.129 CAS number 91195-87-8 Databases IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures RCSB PDB PDBe PDBsum Gene Ontology AmiGO / EGO Search PMC articles PubMed articles NCBI proteins

Function

Neuraminidases, also called sialidases, catalyze the hydrolysis of terminal sialic acid residues from the newly formed 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 man, and strains with N3 or N7 subtypes have been identified in a number of isolated deaths.

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

• Viral neuraminidase
• Bacterial neuraminidase
• Mammalian neuraminidases:

sialidase 1 (lysosomal sialidase) Identifiers Symbol NEU1 Entrez 4758 HUGO 7758 OMIM 608272 RefSeq NM_000434 UniProt Q99519 Other data Locus Chr. 6 p21

sialidase 2 (cytosolic sialidase) Identifiers Symbol NEU2 Entrez 4759 HUGO 7759 OMIM 605528 RefSeq NM_005383 UniProt Q9Y3R4 Other data Locus Chr. 2 q37

sialidase 3 (membrane sialidase) Identifiers Symbol NEU3 Entrez 10825 HUGO 7760 OMIM 604617 RefSeq NM_006656 UniProt Q9UQ49 Other data Locus Chr. 11 q13.5

sialidase 4 Identifiers Symbol NEU4 Entrez 129807 HUGO 21328 OMIM 608527 RefSeq NM_080741 UniProt Q8WWR8 Other data Locus Chr. 2 q37.3

Structure

Main article: Viral neuraminidase

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. β-Sheets predominate as the secondary level of protein conformation.

Recent emergence of oseltamivir and zanamivir resistant human influenza A(H1N1) H274Y has emphasized the need for suitable expression systems to obtain large quantities of highly pure and stable, recombinant neuraminidase through two separate artificial tetramerization domains that facilitate the formation of catalytically active neuraminidase homotetramers from yeast and Staphylothermus marinus, which allow for secretion of FLAG-tagged proteins and further purification.

Mechanism

Proposed mechanism of catalysis of influenza virus sialidase 4 (Link to glycosidase mechanism)

Proposed transition state for the sialidase mechanism 7

Chemical structures of 4- substituted Neu5Ac2en derivatives 8

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

Main article: Neuraminidase 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. 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 [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.

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
• Neuraminidase inhibitors

References

External links

• Neuraminidase at the US National Library of Medicine Medical Subject Headings (MeSH)
• Orthomyxoviruses, Robert B. Couch, UTMB. Article includes a good clear line drawing of a neuraminidase on an influenza virus.

UpToDate Contents

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• 1. インフルエンザに対する抗ウイルス剤の薬理学 pharmacology of antiviral drugs for influenza
• 2. 成人における季節性インフルエンザの治療 treatment of seasonal influenza in adults
• 3. 小児における季節性インフルエンザの予防および治療のための抗ウイルス剤 antiviral drugs for the prevention and treatment of seasonal influenza in children
• 4. 鳥インフルエンザの治療および予防 treatment and prevention of avian influenza
• 5. 成人における季節性インフルエンザの診断 diagnosis of seasonal influenza in adults

English Journal

• Desialylation of dying cells with catalytically active antibodies possessing sialidase activity facilitate their clearance by human macrophages.

• Tomin A1, Dumych T, Tolstyak Y, Kril I, Mahorivska I, Bila E, Stoika R, Herrmann M, Kit Y, Bilyy R.
• Clinical and experimental immunology.Clin Exp Immunol.2015 Jan;179(1):17-23. doi: 10.1111/cei.12312.
• Recently we reported the first known incidence of antibodies possessing catalytic sialidase activity (sialidase abzymes) in the serum of patients with multiple myeloma and systemic lupus erythematosus (SLE). These antibodies desialylate biomolecules, such as glycoproteins, gangliosides and red blood
• PMID 24580640

• Influenza neuraminidase as a vaccine antigen.

• Eichelberger MC1, Wan H.
• Current topics in microbiology and immunology.Curr Top Microbiol Immunol.2015;386:275-99. doi: 10.1007/82_2014_398.
• Neuraminidase (NA) is the second most abundant influenza surface glycoprotein and contributes to virus replication in several ways, most notably by removing sialic acids from the host and viral glycoproteins, releasing newly formed virus particles from infected cells. Antibodies that block this enzy
• PMID 25033754

• Interface dynamics explain assembly dependency of influenza neuraminidase catalytic activity.

• von Grafenstein S1, Wallnoefer HG, Kirchmair J, Fuchs JE, Huber RG, Schmidtke M, Sauerbrei A, Rollinger JM, Liedl KR.
• Journal of biomolecular structure & dynamics.J Biomol Struct Dyn.2015 Jan;33(1):104-20. doi: 10.1080/07391102.2013.855142. Epub 2013 Nov 27.
• Influenza virus neuraminidase (iNA) is a homotetrameric surface protein of the influenza virus and an established target for antiviral drugs. In contrast to neuraminidases (NAs) of other biological systems (non-iNAs), enzymatic activity of iNA is only observed in a quaternary assembly and iNA needs
• PMID 24279589

Japanese Journal

• 抗インフルエンザウイルス薬とその使い方 (特集 インフルエンザとその対策)

• 日本胸部臨床 74(12), 1313-1322, 2015-12
• NAID 40020673349

• 呼吸器内科医からみたインフルエンザ (特集 インフルエンザとその対策)

• 日本胸部臨床 74(12), 1300-1312, 2015-12
• NAID 40020673324

• A型インフルエンザにおけるノイラミニダーゼ阻害薬投与と解熱時間の検討

• 広島医学 68(11), 553-557, 2015-11
• NAID 40020672475

Related Links

• Neuraminidase - Wikipedia, the free encyclopedia

Neuraminidase enzymes are glycoside hydrolase enzymes (EC 3.2.1.18) that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The best-known neuraminidase is ...

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★リンクテーブル★

リンク元	「シアリダーゼ」「sialidase」
拡張検索	「β-galactosidase-neuraminidase deficiency」「neuraminidase inhibitor」「neuraminidase inhibitors」「neuraminidase-inhibiting drug」

「シアリダーゼ」

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英

sialidase

同

ノイラミニダーゼ neuraminidase、α-N-アセチルノイラミニダーゼ α-N-acetylneuraminidase

関

インフルエンザウイルス

「sialidase」

　　[★]

シアリダーゼ

関

neuraminidase

「β-galactosidase-neuraminidase deficiency」

　　[★] β-ガラクトシダーゼ・ノイラミニダーゼ欠乏症

「neuraminidase inhibitor」

　　[★] ノイラミニダーゼ阻害薬

「neuraminidase inhibitors」

　　[★] ノイラミニダーゼ阻害薬

「neuraminidase-inhibiting drug」

　　[★] ノイラミニダーゼ阻害薬