Poly (alpha 2,8-deaminoneuraminic acid) is expressed in lung on a single 150-kDa glycoprotein and is an oncodevelopmental antigen.

Qu, Bao-Xi; Ziak, Martin; Zuber, Christian; Roth, Jürgen

doi:10.1073/pnas.93.17.8995

Cited by 27 publications

(22 citation statements)

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“…The conidia released by the fungus are small enough to reach the lung alveoli, and the resulting disease called invasive aspergillosis occurs predominantly in the lungs. Intriguingly, polyKDN has been found in the human lung, as well as in other tissues, identified through the use of a monoclonal antibody recognizing ␣2,8-linked KDN molecules (4,9). PolyKDN in the lung is a relatively minor component of glycoproteins and glycolipids compared with Neu5Ac and is reported to be associated with a developmentally regulated 150-kDa glycoprotein not present in adults but present in various types of human lung tumors (9).…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, polyKDN has been found in the human lung, as well as in other tissues, identified through the use of a monoclonal antibody recognizing ␣2,8-linked KDN molecules (4,9). PolyKDN in the lung is a relatively minor component of glycoproteins and glycolipids compared with Neu5Ac and is reported to be associated with a developmentally regulated 150-kDa glycoprotein not present in adults but present in various types of human lung tumors (9). The results presented here from a structural analysis of the A. fumigatus KDNase suggest further explorations into its role in nutrition or pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, KDN was first identified in various tissues including human lung carcinoma cells but at a much lower abundances than Neu5Ac (4) and was subsequently found on human red blood cells and ovarian cancer cells (5). The development of linkage-specific KDN antibodies (6,7) has allowed the identification of ␣2,8-linked polyKDN in many mammalian tissues (8), including the human lung (9).…”

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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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“…Sialyltransferases have also been found to be developmentally regulated and differentially expressed among various cell types (1)(2)(3)(4)(5)(6). For example, expression of ␣2-8 linked sialic acids is much less common than ␣2-3 linkages and appears restricted to a small subset of glycoproteins (7)(8)(9)(10).…”

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confidence: 99%

Immune regulation by the ST6Gal sialyltransferase

Hennet

Chui

Paulson

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

328

282

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The ST6Gal sialyltransferase controls production of the Sia␣2-6Gal␤1-4GlcNAc (Sia6LacNAc) trisaccharide, which is the ligand for the lectin CD22. Binding of CD22 to Sia6LacNAc is implicated in regulating lymphocyte adhesion and activation. We have investigated mice that lack ST6Gal and report that they are viable, yet exhibit hallmarks of severe immunosuppression unlike CD22-deficient mice. Notably, Sia6LacNAc-deficient mice display reduced serum IgM levels, impaired B cell proliferation in response to IgM and CD40 crosslinking, and attenuated antibody production to Tindependent and T-dependent antigens. Deficiency of ST6Gal was further found to alter phosphotyrosine accumulation during signal transduction from the B lymphocyte antigen receptor. These studies reveal that the ST6Gal sialyltransferase and corresponding production of the Sia6LacNAc oligosaccharide are essential in promoting B lymphocyte activation and immune function.Sialyltransferases are a family of glycosyltransferase enzymes that add sialic acid residues during oligosaccharide diversification (reviewed in ref. 1). Sialic acid addition occurs in the Golgi apparatus and generally terminates further oligosaccharide chain elongation. The outer position of sialic acid linkages places these residues in a location to provide key structural determinants in ligand formation for endogenous and pathogenic lectins. Three sialic acid linkage types commonly exist among vertebrates and the corresponding sialyltransferase genes have been previously isolated. The most abundant sialic acid linkage found among mammalian cell surface oligosaccharides is of the ␣2-3 variety and can be produced independently by four sialyltransferases that each, nonetheless, bear unique substrate preferences among glycolipids, asparagine (N)-linked glycans, and serine͞threonine (O)-linked glycans (2). Sialyltransferases have also been found to be developmentally regulated and differentially expressed among various cell types (1-6). For example, expression of ␣2-8 linked sialic acids is much less common than ␣2-3 linkages and appears restricted to a small subset of glycoproteins (7-10).␣2-6-linked sialic acids are also less abundant than ␣2-3-linked forms and are generated by at least four distinct gene products. However, the ST6Gal sialyltransferase appears solely responsible for producing the Sia␣2-6Gal␤1-4GlcNAc (Sia6LacNAc) terminus on various N glycans, and perhaps on some O glycans (1, 11). High levels of ST6Gal RNA have been found to preferentially accumulate in hematopoietic cells, as well as in the liver (3-5). Moreover, ST6Gal gene transcription is regulated by multiple promoters and altered by glucocorticoids and cytokines (12)(13)(14). Although the physiologic role of the ST6Gal sialyltransferase has not been defined previously by available genetic approaches, it has been shown to be unique in producing the ligand for the CD22 lectin molecule expressed on B lymphocytes.CD22 is a transmembrane glycoprotein lectin found exclusively on B lymphocytes and is known to p...

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“…1 In this paper, we refer to those with DP equal to or higher than 10 as polymers since they can be differentiated from the homologues of DP Ͻ10 by antibodies, as reported elsewhere, and can be easily prepared by precipitating polylactone from water as shown in this paper. 2 The abbreviations used are: OSA, oligosialic acids; PSA, polysialic acids; HPAEC, high performance anion-exchange chromatography; PAD, pulsed amperometric detection/detector; DP, degree of polymerization; Neu5Ac, 5-N-acetylneuraminic acid; Neu5Gc, 5-N-glycolylneuraminic acid; KDN, 2-keto-3-deoxy-D-glycero-D-galactonononic acid; PSGP, polysialoglycoprotein; 5L 1 , 5L 2 , 5L 3 , etc., lactones of pentameric Neu5Ac with one, two, and three lactone rings per molecule, respectively; GD3, II 3 (NeuAc) 2 -LacCer; GD1b, II such as the positions of the lactone rings and the distribution of different lactone species is difficult to obtain. We have developed a highly sensitive and efficient method for analysis of OSA/PSA using high performance anion-exchange chromatography (HPAEC) and pulsed amperometric detection (PAD) by utilizing either neutral or alkaline conditions for separation (27).…”

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confidence: 99%

Acid-catalyzed Lactonization of α2,8-Linked Oligo/Polysialic Acids Studied by High Performance Anion-exchange Chromatography

Zhang

Lee

1999

Journal of Biological Chemistry

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Recent studies from many laboratories revealed remarkable structural, distributional, and functional diversities of oligo/polysialic acids (OSA/PSA) that exist in organisms ranging from bacteria to man. These diversities are further complicated by the fact that OSA/PSA spontaneously form lactones under even mildly acidic conditions. By using high performance anion-exchange chromatography (HPAEC) with nitrate eluents, we found that lactonization of ␣2,8-linked OSA/PSA (oligo/ poly-Neu5Ac, oligo/poly-Neu5Gc and oligo/poly-KDN) proceeds readily, and the lactonization process displays three discrete stages. The initial stage is characterized by limited lactonization occurring between two internal sialic acid residues, reflected by a regular pattern of lactone peaks interdigitated with non-lactonized peaks on HPAEC. In the middle stage, multiple lactonized species are formed from a molecule with a given degree of polymerization (DP), in which the maximum number of lactone rings formed equals DP minus 2. At the final stage, completely lactonized species become the major components, resulting in drastic changes in the physicochemical properties of the sample. Interestingly, the smallest lactonizable OSA are tetramer, trimer, and dimer at the initial, middle, and final stages, respectively. At any of the stages, OSA/PSA of higher DP lactonize more rapidly, but all the lactone rings rapidly open up when exposed to mild alkali. Lactonized OSA/ PSA are resistant to both enzyme-and acid-catalyzed glycosidic bond cleavage. The latter fact was utilized to obtain more high DP oligo/poly(␣2,8-Neu5Gc) chains from a polysialoglycoprotein. Our results should be useful in preparation, storage, and analysis of OSA/PSA. Possible biological significance and bioengineering potentials of lactonization are discussed.

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Poly (alpha 2,8-deaminoneuraminic acid) is expressed in lung on a single 150-kDa glycoprotein and is an oncodevelopmental antigen.

Cited by 27 publications

References 37 publications

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

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

Immune regulation by the ST6Gal sialyltransferase

Acid-catalyzed Lactonization of α2,8-Linked Oligo/Polysialic Acids Studied by High Performance Anion-exchange Chromatography

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