Metabolic incorporation of unnatural sialic acids into
            <i>Haemophilus ducreyi</i>
            lipooligosaccharides

Goon, Scarlett; Schilling, Birgit; Tullius, Michael V.; Gibson, Bradford W.; Bertozzi, Carolyn R.

doi:10.1073/pnas.0437851100

Cited by 55 publications

(60 citation statements)

References 27 publications

(47 reference statements)

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“…While one cannot generally assume that changes in relative ion abundances of molecular species observed by MS correlate with (23). Therefore, it is with this assumption (and limitations) that relative changes in molecular ion abundances among closely related lipid A species have been used to make semiquantitative arguments regarding the fatty acylation status of lipid A species among the various E. coli and F. tularensis wild-type and mutant strains.…”

Section: Discussionmentioning

confidence: 99%

Identification of LpxL, a Late Acyltransferase of Francisella tularensis

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Identification of LpxL, a Late Acyltransferase of Francisella tularensis

et al. 2007

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“…Because Neu5Gc differs from Neu5Ac by only a single oxygen atom, the human enzymes, transporters, and transferases that normally process Neu5Ac apparently handle exogenous Neu5Gc as if it were a molecule native to human cells. In addition, others have described the processing and incorporation of unnatural Sias into human and bacterial cells (22)(23)(24)(25).…”

Section: Effects Of Natural Human Antibodies Against a Nonhuman Sialimentioning

confidence: 99%

Effects of Natural Human Antibodies against a Nonhuman Sialic Acid That Metabolically Incorporates into Activated and Malignant Immune Cells

Nguyen

Tangvoranuntakul

Varki

2005

The Journal of Immunology

136

144

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Humans are genetically incapable of producing the mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc), due to an inactivating mutation in the enzyme synthesizing it. Despite this, human cells and tissues appear capable of metabolically incorporating Neu5Gc from exogenous sources, including dietary red meat and dairy products. All normal humans studied are now shown to have circulating Abs against Neu5Gc, with marked differences in isotype levels. The question arises whether such Abs can adversely affect Neu5Gc-expressing human cells or tissues. In this study, we show that although normal human PBMC do not incorporate Neu5Gc during in vitro incubation, activated T cells do. Primary human leukemia cells and human leukemic cell lines are even more efficient at incorporation. Human sera containing naturally high levels of anti-Neu5Gc IgG Abs (hereafter abbreviated GcIg) deposited complement on Neu5Gc-expressing leukemic cells and activated T cells, but not on normal cells. The binding of GcIg resulted in complement-mediated cytotoxicity, which was inhibited by heat inactivation. Low anti-Neu5Gc IgG-containing human sera did not mediate any of these effects. Mixed killing assays confirmed the 15-fold selective killing of leukemic cells over PBMC by GcIg following Neu5Gc feeding. This approach could potentially serve as novel way to target malignant cells for death in vivo using either natural Abs or anti-Neu5Gc Abs prepared for this purpose. Further studies are needed to determine whether deposition of natural GcIg and complement can also target healthy proliferating immune cells for death in vivo following incorporation of dietary Neu5Gc.

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“…2). A number of artificial sialic acids have been delivered onto cell surface by this technique (41,42,(46)(47)(48)(49)(50)(51)(52)(53)(54).…”

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Efficient Metabolic Engineering of GM3 on Tumor Cells by N-Phenylacetyl-d-mannosamine

et al. 2006

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Abnormal carbohydrates expressed on tumor cells, which are referred to as tumor-associated carbohydrate antigens (TACAs), are potential targets for development of cancer vaccines. However, immune tolerance to TACAs has severely hindered progress in this area. To overcome this problem, we have developed a novel immunotherapeutic strategy based on synthetic cancer vaccines and metabolic engineering of TACAs on tumor cells. One critical step of this new strategy is metabolic engineering of cancer, namely to induce expression of an artificial form of a TACA by supplying tumors with an artificial monosaccharide precursor. To identify the proper precursor for this application, N-propionyl, N-butanoyl, N-iso-butanoyl and N-phenylacetyl derivatives of Dmannosamine were synthesized, and their efficiency as biosynthetic precursors to modify sialic acid and induce expression of modified forms of GM3 antigen on tumor cells was investigated. For this purpose, tumor cells were incubated with different N-acyl-D-mannosamines, and modified forms of GM3 expressed on tumor cells were analyzed by flow cytometry using antigen-specific antisera. Nphenylacetyl-D-mannosamine was efficiently incorporated in a time and dose dependent manner to bioengineer GM3 expression by several tumor cell lines including K562, SKMEL-28 and B16-F0. Moreover, these tumor cell lines also showed ManPAc-dependent sensitivity to cytotoxicity medicated by anti-PAcGM3 immune serum and complement. These results provide an important validation for this novel therapeutic strategy. Because N-phenylacetyl GM3-protein conjugates are particularly immunogenic, the combination of an N-phenylacetyl GM3 conjugate vaccine with systemic N-phenylacetyl-D-mannosamine treatment is a promising immunotherapy for future development and application to melanoma and other GM3-bearing tumors. KeywordsMetabolic engineering; cancer vaccine; GM3; D-mannosamine; sialic acid Sialic acids are unique nine-carbon acidic monosaccharides ubiquitously distributed in high animals and human beings (1). The most common form of sialic acids is N-acetyl-D-neuraminic acid (Neu5Ac, also knows as N-acetyl sialic acid). Neu5Ac is a fascinating sugar in that it usually appears at the nonreducing end of cell surface glycans and thus plays forefront roles in various biological functions such as cell proliferation, immune recognition and pathogenic invasion (2-8).

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Metabolic incorporation of unnatural sialic acids into Haemophilus ducreyi lipooligosaccharides

Cited by 55 publications

References 27 publications

Identification of LpxL, a Late Acyltransferase of Francisella tularensis

Identification of LpxL, a Late Acyltransferase of Francisella tularensis

Effects of Natural Human Antibodies against a Nonhuman Sialic Acid That Metabolically Incorporates into Activated and Malignant Immune Cells

Efficient Metabolic Engineering of GM3 on Tumor Cells by N-Phenylacetyl-d-mannosamine

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