Influenza B virus neuraminidase can synthesize its own inhibitor

Burmeister, W.P.; Henrissat, Bernard; Bosso, C.; Cusack, Stephen; Ruigrok, Rob W.H.

doi:10.1016/0969-2126(93)90005-2

Cited by 145 publications

(138 citation statements)

References 22 publications

Supporting

Mentioning

132

Contrasting

Order By: Relevance

“…cruzi TS is an unusual sialidase with a predominant transglycosylase activity (21). The catalytic mechanism of trypanosomal sialidase (11) seems to be similar to viral sialidase (22) which is thought to hydrolyze the sialyl glycosidic bound through an oxocarbenium ion intermediate, with formation of trace amount of 2-deoxy-2,3-didehydro-N-acetylneuraminic (Neu5Ac2en) as a by-product. The predominance of transglycosylation over hydrolysis can be explained by the presence of distinct binding sites for acceptor and donor substrates in the TS catalytic pocket.…”

Section: Discussionmentioning

confidence: 99%

Enzymatically Inactive trans-Sialidase from Trypanosoma cruzi Binds Sialyl and β-Galactopyranosyl Residues in a Sequential Ordered Mechanism

Todeschini

Dias

Girard

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Host/parasite interaction mediated by carbohydrate/ lectin recognition results in the attachment to and invasion of host cells and immunoregulation, enabling parasite replication and establishment of infection. Trypanosoma cruzi, the protozoan responsible for Chagas disease, expresses on its surface a family of enzymatically active and inactive trans-sialidases. The parasite uses the active trans-sialidase for glycoprotein sialylation in an unusual trans-glycosylation reaction. Inactive trans-sialidase is a sialic acid-binding lectin that costimulates host T cells through leucosialin (CD43) engagement. The co-mitogenic effect of trans-sialidase can be selectively abrogated by N-acetyllactosamine, suggesting the presence of an additional carbohydrate binding domain for galactosides, in addition to that for sialic acid. Here we investigated the interaction of inactive trans-sialidase in the presence of ␤-galactosides. By using NMR spectroscopy, we demonstrate that inactive trans-sialidase has a ␤-galactoside recognition site formed following a conformational switch induced by sialoside binding. Thus prior positioning of a sialyl residue is required for the ␤-galactoside interaction. When an appropriate sialic acid-containing molecule is available, both sialoside and ␤-galactoside are simultaneously accommodated in the inactive trans-sialidase binding pocket. This is the first report of a lectin recognizing two distinct ligands by a sequential ordered mechanism. This uncommon binding behavior may play an important role in several biological aspects of T. cruzi/host cell interaction and could shed more light into the catalytic mechanism of the sialic acid transfer reaction of enzymatically active trans-sialidase.Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis that affects ϳ18 million people in Central and South America. Another 100 million people are at risk of infection (1). Mammalian cell invasion is crucial for T. cruzi survival (2). Elucidation of molecular components regulating the initiation of the parasitic infection is critical for understanding the pathogenesis of Chagas disease and will enable the development of novel, effective, and selective treatments.Initial communication between T. cruzi trypomastigotes and mammalian cells requires contact of soluble or membranebound parasite molecules with host ligands. T. cruzi expresses on its surface a family of glycosylphosphatidylinositol-anchored active and inactive trans-sialidase (TS) 1 proteins (3-5), which contain a Tyr or a His residue, respectively, at position 342 (4). The parasite uses active TS to sialylate its surface glycoproteins by a trans-sialidase reaction (6). Thus, TS activity is capable of extensively remodeling the T. cruzi cell surface by using host glycoconjugates as sialyl donor. Alternatively, the enzyme may sialylate host cell glycomolecules to generate receptors used by the trypanosome for adherence to and penetration of target cells. Results with sialic acid-deficient mutants of Chinese hamster ov...

show abstract

Section: Discussionmentioning

confidence: 99%

Enzymatically Inactive trans-Sialidase from Trypanosoma cruzi Binds Sialyl and β-Galactopyranosyl Residues in a Sequential Ordered Mechanism

Todeschini

Dias

Girard

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Under a variety of soaking conditions, sialic acid was seen bound in both the active site and the HB site of all four monomers. In the active site the sialic acid is in the twisted boat conformation that may result from its tight binding preceding catalysis 22,63,64 , while the sialic acid in the HB site is in the chair conformation as in N9 NB site and in HA 32,59 . Interestingly, although sialic acid in solution exists 95% as the β anomer, only the α configuration is seen in the HB binding site (Figure 3), which may explain the difficulty in locating the second sialic acid in N9 NA and the high concentration of sialic acid needed before the sialic acid is clearly seen.…”

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

Influenza neuraminidase

Air

2011

Influenza Resp Viruses

208

216

View full text Add to dashboard Cite

Influenza neuraminidase is the target of two licensed antivirals that have been very successful, with several more in development. However, neuraminidase has been largely ignored as a vaccine target despite evidence that inclusion of neuraminidase in the subunit vaccine gives increased protection. This article describes current knowledge on the structure, enzyme activity and antigenic significance of neuraminidase.

show abstract

“…Leaving group effect and kinetic isotope effect experiments with influenza NA carried out by Guo et al 16 and Chou et al 20 are compatible with the classical mechanism that includes a covalent enzyme-sialosyl intermediate. Studies by Burmeister et al 21 and Ghate et al 22 also suggest that Tyr406 has an important role in the influenza NA mechanism. However, numerous studies still indicate that the influenza NA may possibly function in a unique manner.…”

mentioning

confidence: 93%