Biosynthetic incorporation of unnatural sialic acids into polysialic acid on neural cells

Charter, Neil W.; Mahal, Lara K.; Koshland, Daniel E.; Bertozzi, Carolyn R.

doi:10.1093/glycob/10.10.1049

Cited by 38 publications

(33 citation statements)

References 41 publications

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“…With regard to ST8SiaII and -IV, the situation is less clear. Although they have been found to be variably active on a number of unnatural sialic acids (93)(94)(95)(96), their activity on CMP-Neu5Gc has not been reported.…”

Section: Resultsmentioning

confidence: 99%

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

Davies

Pearce

Tessier

et al. 2012

Journal of Biological Chemistry

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Background:The sialic acid N-glycolylneuraminic acid (Neu5Gc) shows conserved suppression of expression in vertebrate brains, suggesting brain-specific toxicity. Results: ␣2-8-Linked Neu5Gc incorporated into the neural glycan polysialic acid (polySia) resists sialidase breakdown through conformational effects. Conclusion: Neu5Gc in brain would prevent rapid turnover of surface polySia. Significance: This mechanism potentially underlies the evolutionary suppression of Neu5Gc expression in vertebrate brains.

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Section: Resultsmentioning

confidence: 99%

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

Davies

Pearce

Tessier

et al. 2012

Journal of Biological Chemistry

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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

137

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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“…In fact, hyposialylated, Gne-deficient mouse embryonic stem cells became resialylated after their growth medium was supplemented with ManNAc (16). Furthermore, incubation of cultured cells with "unnatural" ManNAc derivatives, i.e., N-levulinoylmannosamine (ManLev) or N-azidoacetylmannosamine (ManNAz), resulted in incorporation of the downstream sialic acid analogs (SiaLev or SiaNAz) into cell surface glycoconjugates (20). Importantly, oral supplementation of 14 C-ManNAc to healthy rats showed incorporation of the 14 C label into several tissues, including kidney and muscle (21).…”

Section: Introductionmentioning

confidence: 99%

Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine

Galeano¹,

Klootwijk²,

Manoli³

et al. 2007

J. Clin. Invest.

181

179

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Mutations in the key enzyme of sialic acid biosynthesis, uridine diphospho-N-acetylglucosamine 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), result in hereditary inclusion body myopathy (HIBM), an adult-onset, progressive neuromuscular disorder. We created knockin mice harboring the M712T Gne/Mnk mutation. Homozygous mutant (Gne M712T/M712T ) mice did not survive beyond P3. At P2, significantly decreased Gne-epimerase activity was observed in Gne M712T/M712T muscle, but no myopathic features were apparent. Rather, homozygous mutant mice had glomerular hematuria, proteinuria, and podocytopathy. Renal findings included segmental splitting of the glomerular basement membrane, effacement of podocyte foot processes, and reduced sialylation of the major podocyte sialoprotein, podocalyxin. ManNAc administration yielded survival beyond P3 in 43% of the Gne M712T/M712T pups. Survivors exhibited improved renal histology, increased sialylation of podocalyxin, and increased Gne/Mnk protein expression and Gneepimerase activities. These findings establish this Gne M712T/M712T knockin mouse as what we believe to be the first genetic model of podocyte injury and segmental glomerular basement membrane splitting due to hyposialylation. The results also support evaluation of ManNAc as a treatment not only for HIBM but also for renal disorders involving proteinuria and hematuria due to podocytopathy and/or segmental splitting of the glomerular basement membrane.

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Biosynthetic incorporation of unnatural sialic acids into polysialic acid on neural cells

Cited by 38 publications

References 41 publications

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

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

Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine

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