Multivalency and the Mode of Action of Bacterial Sialidases

Thobhani, Smita; Ember, Brian; Siriwardena, Aloysius; Boons, Geert‐Jan

doi:10.1021/ja029759w

Cited by 64 publications

(63 citation statements)

References 17 publications

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“…[51][52][53][54] This particular bacterial neuraminidase was chosen because it (like human Neu1) preferentially removes terminal sialic acids from monovalent sialylated glycoproteins but not from sialylated gangliosides, as other bacterial sialidases do. We anticipated that the biological effects observed after treatment of cultured SMCs with the C. perfringens neuraminidase would differ from the effects recorded after treatment with Vibrio cholerae neuraminidase, [55][56][57] which preferentially hydrolyzes both Ϫ2,3-and Ϫ2,6-linked sialic acid residues from higher-order gangliosides.…”

Section: Cell Culturesmentioning

confidence: 99%

Neuraminidase-1, a Subunit of the Cell Surface Elastin Receptor, Desialylates and Functionally Inactivates Adjacent Receptors Interacting with the Mitogenic Growth Factors PDGF-BB and IGF-2

Hinek

Bodnaruk

Bunda

et al. 2008

The American Journal of Pathology

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We recently established that the elastin-binding protein, which is identical to the spliced variant of ␤-galactosidase, forms a cell surface-targeted complex with two proteins considered "classic lysosomal enzymes": protective protein/cathepsin A and neuraminidase-1 (Neu1). We also found that cell surface-residing Neu1 can desialylate neighboring microfibrillar glycoproteins and facilitate the deposition of insoluble elastin, which contributes to the maintenance of cellular quiescence. Here we provide evidence that cell surfaceresiding Neu1 contributes to a novel mechanism that limits cellular proliferation by desialylating cell membrane-residing sialoglycoproteins that directly propagate mitogenic signals. We demonstrated that treatment of cultured human aortic smooth muscle cells (SMCs) with either a sialidase inhibitor or an antibody that blocks Neu1 activity induced significant up-regulation in SMC proliferation in response to fetal bovine serum. Conversely, treatment with Clostridium perfringens neuraminidase (which is highly homologous to Neu1) decreased SMC proliferation, even in cultures that did not deposit elastin. Further, we found that pretreatment of aortic SMCs with exogenous neuraminidase abolished their mitogenic responses to recombinant platelet-derived growth factor (PDGF)-BB and insulin-like growth factor (IGF)-2 and that sialidosis fibroblasts (which are exclusively deficient in Neu1) were more responsive to PDGF-BB and IGF-2 compared with normal fibroblasts. Furthermore , we provide direct evidence that neuraminidase caused the desialylation of both PDGF and IGF-1 receptors and diminished the intracellular signals induced by the mitogenic ligands

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Section: Cell Culturesmentioning

confidence: 99%

Neuraminidase-1, a Subunit of the Cell Surface Elastin Receptor, Desialylates and Functionally Inactivates Adjacent Receptors Interacting with the Mitogenic Growth Factors PDGF-BB and IGF-2

Hinek

Bodnaruk

Bunda

et al. 2008

The American Journal of Pathology

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“…Like many glycosyl hydrolases, sialidases can possess carbohydrate-binding modules (CBMs) in addition to the catalytic domain, placed upstream, placed downstream, or even inserted within the ␤-propeller domain. It has been suggested that the presence of these CBMs increases the catalytic efficiency of the sialidases, particularly in the presence of polysaccharide substrates (25). In the case of sialidases having CBMs, they often recognize sialic acid as has been shown for the sialidases from Vibrio cholerae (26), Clostridium perfringens (27), and Streptococcus pneumoniae (15).…”

mentioning

confidence: 96%

The Aspergillus fumigatus Sialidase Is a 3-Deoxy-d-glycero-d-galacto-2-nonulosonic Acid Hydrolase (KDNase)

Telford

Yeung²,

et al. 2011

Journal of Biological Chemistry

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Aspergillus fumigatus is a filamentous fungus that can cause severe respiratory disease in immunocompromised individuals. A putative sialidase from A. fumigatus was recently cloned and shown to be relatively poor in cleaving N-acetylneuraminic acid (Neu5Ac) in comparison with bacterial sialidases. Here we present the first crystal structure of a fungal sialidase. When the apo structure was compared with bacterial sialidase structures, the active site of the Aspergillus enzyme suggested that Neu5Ac would be a poor substrate because of a smaller pocket that normally accommodates the acetamido group of Neu5Ac in sialidases. A sialic acid with a hydroxyl in place of an acetamido group is 2-keto-3-deoxynononic acid (KDN). We show that KDN is the preferred substrate for the A. fumigatus sialidase and that A. fumigatus can utilize KDN as a sole carbon source. A 1.45-Å resolution crystal structure of the enzyme in complex with KDN reveals KDN in the active site in a boat conformation and nearby a second binding site occupied by KDN in a chair conformation, suggesting that polyKDN may be a natural substrate. The enzyme is not inhibited by the sialidase transition state analog 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) but is inhibited by the related 2,3-didehydro-2,3-dideoxy-D-glycero-D-galacto-nonulosonic acid that we show bound to the enzyme in a 1.84-Å resolution crystal structure. Using a fluorinated KDN substrate, we present a 1.5-Å resolution structure of a covalently bound catalytic intermediate. The A. fumigatus sialidase is therefore a KDNase with a similar catalytic mechanism to Neu5Ac exosialidases, and this study represents the first structure of a KDNase.

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“…Many sialidases possess domains in addition to the catalytic domain, placed upstream, downstream, or even inserted within the ␤-propeller domain; the Vibrio cholerae sialidase has two lectin domains flanking the catalytic domain, one of which binds sialic acid (18); Micromonospora viridifaciens sialidase has a galactose-binding domain C-terminal to the catalytic domain and is positioned above the active site (20); the leech sialidase has a lectin-like domain N-terminal to the catalytic domain (15), and the trypanosome (trans-) sialidases have a lectin-like domain C-terminal to the catalytic domain (13,14). It has been suggested that the presence of these carbohydratebinding modules increases the catalytic efficiency of the sialidases, particularly in the presence of polysaccharide substrates (21). Many glycoside hydrolases have additional carbohydratebinding modules, particularly those involved in the degradation of insoluble polysaccharides such as cellulose and starch, and these carbohydrate-binding modules show a great diversity in ligand recognition and folds (22).…”

mentioning

confidence: 99%

The Structure of Clostridium perfringens NanI Sialidase and Its Catalytic Intermediates

Newstead

Potter

Wilson

et al. 2008

Journal of Biological Chemistry

108

106

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Clostridium perfringens is a Gram-positive bacterium responsible for bacteremia, gas gangrene, and occasionally food poisoning. Its genome encodes three sialidases, nanH, nanI, and nanJ, that are involved in the removal of sialic acids from a variety of glycoconjugates and that play a role in bacterial nutrition and pathogenesis. Recent studies on trypanosomal (trans-) sialidases have suggested that catalysis in all sialidases may proceed via a covalent intermediate similar to that of other retaining glycosidases. Here we provide further evidence to support this suggestion by reporting the 0.97 Å resolution atomic structure of the catalytic domain of the C. perfringens NanI sialidase, and complexes with its substrate sialic acid (N-acetylneuramic acid) also to 0.97 Å resolution, with a transition-state analogue (2-deoxy-2,3-dehydro-N-acetylneuraminic acid) to 1.5 Å resolution, and with a covalent intermediate formed using a fluorinated sialic acid analogue to 1.2 Å resolution. Together, these structures provide high resolution snapshots along the catalytic pathway. The crystal structures suggested that NanI is able to hydrate 2-deoxy-2,3-dehydro-N-acetylneuraminic acid to N-acetylneuramic acid. This was confirmed by NMR, and a mechanism for this activity is suggested.

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Multivalency and the Mode of Action of Bacterial Sialidases

Cited by 64 publications

References 17 publications

Neuraminidase-1, a Subunit of the Cell Surface Elastin Receptor, Desialylates and Functionally Inactivates Adjacent Receptors Interacting with the Mitogenic Growth Factors PDGF-BB and IGF-2

Neuraminidase-1, a Subunit of the Cell Surface Elastin Receptor, Desialylates and Functionally Inactivates Adjacent Receptors Interacting with the Mitogenic Growth Factors PDGF-BB and IGF-2

The Aspergillus fumigatus Sialidase Is a 3-Deoxy-d-glycero-d-galacto-2-nonulosonic Acid Hydrolase (KDNase)

The Structure of Clostridium perfringens NanI Sialidase and Its Catalytic Intermediates

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