Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

Davies, Leela R.L.; Pearce, Oliver M.T.; Tessier, Matthew B.; Assar, Siavash; Smutova, Victoria; Pajunen, Maria I.; Sumida, Mizuki; Sato, Chihiro; Kitajima, Ken; Finne, Jukka; Gagneux, Pascal; Pshezhetsky, Alexey V.; Woods, Robert J.; Varki, Ajit

doi:10.1074/jbc.m112.365056

Cited by 45 publications

(34 citation statements)

References 105 publications

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“…Unlike the highly variable levels of Neu5Gc found in all other tissues, the suppression of brain Neu5Gc expression is remarkably conserved across all vertebrates that have been studied to date (see Table 1, reproduced from [32]). The highest published fraction of Neu5Gc in brain tissue is 10% in a sample of adult bovine neocortex and 5% in calf [33].…”

Section: Rarity Of Neu5gc In the Vertebrate Brainmentioning

confidence: 99%

“…It is interesting to note here that polysialyltransferases are able to incorporate a number of unnatural sialic acids into polySia [101, 102]. Recently, our laboratory has demonstrated that cells from a murine neuroblastoma line are similarly able to incorporate Neu5Gc into endogenous polySia [32]. Although polymers of Neu5Gc are found in the glycoproteins of the eggs of salmonid fish [103], Neu5Gc has never been reported in mammalian polysialic acid, neural or otherwise.…”

Section: Claims For Presence Of Neu5gc In Neural Tissuesmentioning

confidence: 99%

“…Indeed, a recent paper from our own laboratory demonstrated that Neu5Gc is relatively resistant to degradation by sialidase when present in the α2-8 linkage common in brain glycans, including polySia [32]. This phenomenon may allow for a very small fraction of Neu5Gc to be highly detrimental to the brain, as an entire chain of polySia can be rendered resistant to breakdown by the presence of a terminal Neu5Gc.…”

Section: Possible Mechanisms For the Presumed Toxicity Of Neu5gc Inmentioning

confidence: 99%

“…Neu5Ac and Neu5Gc fractions of samples in our lab were determined by total acid hydrolysis of tissue lysate followed by DMB-HPLC. Conserved suppression of Neu5Gc in the brain is unusual among vertebrate tissues ++: major fraction; +: minor fraction; –: absent; trace: present at 0.8–3%; nr: not reported a Data from our laboratory b Published data confirmed in our laboratory This research was originally published in [32]. © The American Society for Biochemistry and Molecular Biology…”

Section: Figmentioning

confidence: 99%

“…This research was originally published in [32]. © The American Society for Biochemistry and Molecular Biology…”

Section: Figmentioning

confidence: 99%

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Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain?

Davies

Varki

2013

Topics in Current Chemistry

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The sialic acids N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) differ by a single oxygen atom and are widely found at the terminal position of glycans on vertebrate cell surfaces. In animals capable of synthesizing Neu5Gc, most tissues and cell types express both sialic acids, in proportions that vary between species. However, it has long been noted that Neu5Gc is consistently expressed at trace to absent levels in the brains of all vertebrates studied to date. Although several reports have claimed to find low levels of Neu5Gc-containing glycans in neural tissue, no study definitively excludes the possibility of contamination with glycans from non-neural cell types. This distribution of a molecule – prominently but variably expressed in extraneural tissues but very low or absent in the brain – is, to our knowledge, unique. The evolutionarily conserved brain-specific suppression of Neu5Gc may indicate that its presence is toxic to this organ; however, no studies to date have directly addressed this very interesting question. Here we provide a historical background to this issue and discuss potential mechanisms causing the suppression of Neu5Gc expression in brain tissue, as well as mechanisms by which Neu5Gc may exert the presumed toxicity. Finally, we discuss future approaches towards understanding the mechanisms and implications of this unusual finding.

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Section: Rarity Of Neu5gc In the Vertebrate Brainmentioning

confidence: 99%

Section: Claims For Presence Of Neu5gc In Neural Tissuesmentioning

confidence: 99%

Section: Possible Mechanisms For the Presumed Toxicity Of Neu5gc Inmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

“…This research was originally published in [32]. © The American Society for Biochemistry and Molecular Biology…”

Section: Figmentioning

confidence: 99%

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Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain?

Davies

Varki

2013

Topics in Current Chemistry

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Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N‐Glycolylneuraminic Acid

Okerblom

Varki

2017

ChemBioChem

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About 2–3 million years ago, Alu‐mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans, possibly through a stepwise process of selection by pathogen targeting of the CMAH product (the sialic acid Neu5Gc), followed by reproductive isolation through female anti‐Neu5Gc antibodies. Loss of CMAH has occurred independently in some other lineages, but is functionally intact in Old World primates, including our closest relatives, the chimpanzee. Although the biophysical and biochemical ramifications of losing tens of millions of Neu5Gc hydroxy groups at most cell surfaces remains poorly understood, we do know that there are multiscale effects functionally relevant to both sides of the host–pathogen interface. Hominin CMAH loss might also contribute to understanding human evolution, at the time when our ancestors were starting to use stone tools, increasing their consumption of meat, and possibly hunting. Comparisons with chimpanzees within ethical and practical limitations have revealed some consequences of human CMAH loss, but more has been learned by using a mouse model with a human‐like Cmah inactivation. For example, such mice can develop antibodies against Neu5Gc that could affect inflammatory processes like cancer progression in the face of Neu5Gc metabolic incorporation from red meats, display a hyper‐reactive immune system, a human‐like tendency for delayed wound healing, late‐onset hearing loss, insulin resistance, susceptibility to muscular dystrophy pathologies, and increased sensitivity to multiple human‐adapted pathogens involving sialic acids. Further studies in such mice could provide a model for other human‐specific processes and pathologies involving sialic acid biology that have yet to be explored.

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Detection Strategies for Sialic Acid and Sialoglycoconjugates

Hunter,

Cairo

2024

ChemBioChem

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Glycoconjugates are a vast class of biomolecules implicated in biological processes important for human health and disease. The structural complexity of glycoconjugates remains a challenge to deciphering their precise biological roles and for their development as biomarkers and therapeutics. Human glycoconjugates on the outside of the cell are modified with sialic (neuraminic) acid residues at their termini. The enzymes that install sialic acids are sialyltransferases (SiaTs), a family of 20 different isoenzymes. The removal and degradation of sialic acids is mediated by neuraminidase (NEU; sialidase) enzymes, of which there are four isoenzymes. In this review, we discuss chemical and biochemical approaches for the detection and analysis of sialoglycoconjugate (SGC) structures and their enzymatic products. The most common methods include affinity probes and synthetic substrates. Fluorogenic and radiolabelled substrates are also important tools for many applications, including screening for enzyme inhibitors. Strategies that give insight into the native substrate‐specificity of enzymes that regulate SGCs (SiaT & NEU) are necessary to improve our understanding of the role of sialic acid metabolism in health and disease.

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Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

Cited by 45 publications

References 105 publications

Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain?

Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain?

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N‐Glycolylneuraminic Acid

Detection Strategies for Sialic Acid and Sialoglycoconjugates

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