N-Glycolylneuraminic acid in human tumours***Dedicated to Prof. Dr. Yoshitaka Nagai on the occasion of his 70th birthday.

Malykh, Yanina N.; Schauer, Roland; Shaw, Lee

doi:10.1016/s0300-9084(01)01303-7

Cited by 250 publications

(101 citation statements)

References 79 publications

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“…This result also demonstrates that at least in tissue culture free NeuGc can be taken up and incorporated by human cells. It has been suggested that NeuGc found in human cells in the absence of endogenous biosynthesis might originate from alimentary or intestinal microbial sources (64,65). Little is known about the mechanism of sialic acid resorption, but our findings suggest that also in vivo free NeuGc, once present in the extracellular space, could be taken up directly by cells.…”

Section: Discussionmentioning

confidence: 55%

Versatile Biosynthetic Engineering of Sialic Acid in Living Cells Using Synthetic Sialic Acid Analogues

Oetke

Brossmer

Mantey

et al. 2002

Journal of Biological Chemistry

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Sialic acids are critical components of many glycoconjugates involved in biologically important ligand-receptor interactions. Quantitative and structural variations of sialic acid residues can profoundly affect specific cellcell, pathogen-cell, or drug-cell interactions, but manipulation of sialic acids in mammalian cells has been technically limited. We describe the finding of a previously unrecognized and efficient uptake and incorporation of sialic acid analogues in mammalian cells. We added 16 synthetic sialic acid analogues carrying distinct C-1, C-5, or C-9 substitutions individually to cell cultures of which 10 were readily taken up and incorporated. Uptake of C-5-and C-9-substituted sialic acids resulted in the structural modification of up to 95% of sialic acids on the cell surface. Functionally, binding of murine sialic acid-binding immunoglobulin-like lectin-2 (Siglec-2, CD22) to cells increased after N-glycolylneuraminic acid treatment, whereas 9-iodo-N-acetylneuraminic acid abolished binding. Furthermore, susceptibility to infection by the B-lymphotropic papovavirus via a sialylated receptor was markedly enhanced following pretreatment of host cells with selected sialic acid analogues including 9-iodo-N-acetylneuraminic acid. This novel experimental strategy allows for an efficient biosynthetic engineering of surface sialylation in living cells. It is versatile, extending the repertoire of modification sites at least to C-9 and enables detailed structure-function studies of sialic acid-dependent ligand-receptor interactions in their native context.

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Section: Discussionmentioning

confidence: 55%

Versatile Biosynthetic Engineering of Sialic Acid in Living Cells Using Synthetic Sialic Acid Analogues

Oetke

Brossmer

Mantey

et al. 2002

Journal of Biological Chemistry

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“…Some authors have suggested that the increased levels of sialic acids associated with the tumour membrane surface may contribute to this selectivity [12]. These acids are negatively charged sugar residues that usually occupy exposed terminal positions on the oligosaccharide chains of membrane bound glycoconjugates [74]. This suggestion was strongly supported when it was found that the pre-treatment of tumour cells with neuraminidase to enzymatically digest sialyl residues and remove them from the cell surface greatly reduced the ability of several α-ACPs to target these membranes [75].…”

Section: The Selectivity Of α-Acps For Cancer Cellsmentioning

confidence: 99%

Anticancer α-Helical Peptides and Structure / Function Relationships Underpinning Their Interactions with Tumour Cell Membranes

Dennison¹,

Whittaker²,

Harris³

et al. 2006

CPPS

151

162

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Cancer is a major cause of premature death and there is an urgent need for new anticancer agents with novel mechanisms of action. Here we review recent studies on a group of peptides that show much promise in this regard, exemplified by arthropod cecropins and amphibian magainins and aureins. These molecules are alpha-helical defence peptides, which show potent anticancer activity (alpha-ACPs) in addition to their established roles as antimicrobial factors and modulators of innate immune systems. Generally, alpha-ACPs exhibit selectivity for cancer and microbial cells primarily due to their elevated levels of negative membrane surface charge as compared to non-cancerous eukaryotic cells. The anticancer activity of alpha-ACPs normally occurs at micromolar levels but is not accompanied by significant levels of haemolysis or toxicity to other mammalian cells. Structure/function studies have established that architectural features of alpha-ACPs such as amphiphilicty levels and hydrophobic arc size are of major importance to the ability of these peptides to invade cancer cell membranes. In the vast majority of cases the mechanisms underlying such killing involves disruption of mitochondrial membrane integrity and/or that of the plasma membrane of the target tumour cells. Moreover, these mechanisms do not appear to proceed via receptor-mediated routes but are thought to be effected in most cases by the carpet/toroidal pore model and variants. Usually, these membrane interactions lead to loss of membrane integrity and cell death utilising apoptic and necrotic pathways. It is concluded that that alpha-ACPs are major contenders in the search for new anticancer drugs, underlined by the fact that a number of these peptides have been patented in this capacity.

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“…1 This tumor marker is expressed in certain tumor cells, such as melanoma and breast tumors (2,3), but is otherwise absent from normal human tissues (4), which opens up the possibility of using antibodies specific toward these molecules both for diagnosis and immunotherapy.…”

mentioning

confidence: 99%

Structure and Molecular Interactions of a Unique Antitumor Antibody Specific for N-Glycolyl GM3

Krengel

Olsson

Martínez

et al. 2004

Journal of Biological Chemistry

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N-Glycolyl GM3 ganglioside is an attractive target antigen for cancer immunotherapy, because this epitope is a molecular marker of certain tumor cells and not expressed in normal human tissues. The murine monoclonal antibody 14F7 specifically recognizes N-glycolyl GM3 and shows no cross-reactivity with the abundant N-acetyl GM3 ganglioside, a close structural homologue of N-glycolyl GM3. Here, we report the crystal structure of the 14F7 Fab fragment at 2.5 Å resolution and its molecular model with the saccharide moiety of N-glycolyl GM3, NeuGc␣3Gal␤4Glc␤. Fab 14F7 contains a very long CDR H3 loop, which divides the antigen-binding site of this antibody into two subsites. In the docking model, the saccharide ligand is bound to one of these subsites, formed solely by heavy chain residues. The discriminative feature of N-glycolyl GM3 versus N-acetyl GM3, its hydroxymethyl group, is positioned in a hydrophilic cavity, forming hydrogen bonds with the carboxyl group of Asp H52, the indole NH of Trp H33 and the hydroxyl group of Tyr H50. For the hydrophobic methyl group of N-acetyl GM3, this environment would not be favorable, explaining why the antibody specifically recognizes N-glycolyl GM3, but not N-acetyl GM3. Mutation of Asp H52 to hydrophobic residues of similar size completely abolished binding. Our model of the antibodycarbohydrate complex is consistent with binding data for several tested glycolipids as well as for a variety of 14F7 mutants with replaced VL domains.

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N-Glycolylneuraminic acid in human tumours***Dedicated to Prof. Dr. Yoshitaka Nagai on the occasion of his 70th birthday.

Cited by 250 publications

References 79 publications

Versatile Biosynthetic Engineering of Sialic Acid in Living Cells Using Synthetic Sialic Acid Analogues

Versatile Biosynthetic Engineering of Sialic Acid in Living Cells Using Synthetic Sialic Acid Analogues

Anticancer α-Helical Peptides and Structure / Function Relationships Underpinning Their Interactions with Tumour Cell Membranes

Structure and Molecular Interactions of a Unique Antitumor Antibody Specific for N-Glycolyl GM3

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N-Glycolylneuraminic acid in human tumours***Dedicated to Prof. Dr. Yoshitaka Nagai on the occasion of his 70th birthday.

Cited by 250 publications

References 79 publications

Versatile Biosynthetic Engineering of Sialic Acid in Living Cells Using Synthetic Sialic Acid Analogues

Versatile Biosynthetic Engineering of Sialic Acid in Living Cells Using Synthetic Sialic Acid Analogues

Anticancer &#945;-Helical Peptides and Structure / Function Relationships Underpinning Their Interactions with Tumour Cell Membranes

Structure and Molecular Interactions of a Unique Antitumor Antibody Specific for N-Glycolyl GM3

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Product

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Anticancer α-Helical Peptides and Structure / Function Relationships Underpinning Their Interactions with Tumour Cell Membranes