Sialylation of N-glycans: mechanism, cellular compartmentalization and function

Bhide, Gaurang P.; Colley, Karen J.

doi:10.1007/s00418-016-1520-x

Cited by 182 publications

(151 citation statements)

References 268 publications

(346 reference statements)

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“…1 In mammals, sialic acids usually serve as the terminal monosaccharides of the glycans in glycoproteins and glycolipids. 1 In mammals, sialic acids usually serve as the terminal monosaccharides of the glycans in glycoproteins and glycolipids.…”

Section: Introductionmentioning

confidence: 99%

ST3GAL3, ST3GAL4, and ST3GAL6 differ in their regulation of biological functions via the specificities for the α2,3‐sialylation of target proteins

Isaji

Duan

et al. 2019

FASEB j.

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The α2,3‐sialylation of N‐glycans is considered important but complicated because the functions of the three β‐galactoside α2,3‐sialyltransferases, ST3GAL3, ST3GAL4, and ST3GAL6, could be compensating for one another. To distinguish their specific functions, we established each individual knockout (KO) cell line. Loss of either the ST3GAL3 or ST3GAL6 genes decreased cell proliferation and colony formation, as opposed to the effect in the ST3GAL4 KO cells. The phosphorylation levels of ERK and AKT were significantly suppressed in the ST3GAL6 KO and ST3GAL3 KO cells, respectively. The cell aggregations were clearly observed in the KO cells, particularly the ST3GAL3 KO and ST3GAL6 KO cells, and the expression levels of E‐cadherin and claudin‐1 were enhanced in both those cell lines, but were suppressed in the ST3GAL4 KO cells. Those alterations were reversed with an overexpression of each corresponding gene in rescued cells. Of particular interest, the α2,3‐sialylation levels of β1 integrin were clearly suppressed in the ST3GAL4 KO cells, but these were increased in the ST3GAL3 KO and ST3GAL6 KO cells, whereas the α2,3‐sialylation levels of EGFR were significantly decreased in the ST3GAL6 KO cells. The decrease in α2,3‐sialylation increased the α2,6‐sialylation on β1, but not EGFR. Furthermore, a cross‐restoration of each of the three genes in ST3GAL6 KO cells showed that overexpression of ST3GAL6 sufficiently rescued the total α2,3‐sialylation levels, cell morphology, and α2,3‐sialylation of EGFR, whereas the α2,3‐sialylation levels of β1 were greatly enhanced by an overexpression of ST3GAL4. These results clearly demonstrate that the three α2,3‐sialyltransferases modify characteristic target proteins and regulate cell biological functions in different ways.

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Section: Introductionmentioning

confidence: 99%

ST3GAL3, ST3GAL4, and ST3GAL6 differ in their regulation of biological functions via the specificities for the α2,3‐sialylation of target proteins

Isaji

Duan

et al. 2019

FASEB j.

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“…This enzyme catalyzes the rate-limiting step in the biosynthesis of sialic acid (N-acetylneuraminic acid; Neu5Ac) [5], which enters the nucleus to become activated into cytidine-5′-monophospho-N-acetylneuraminic acid (CMP-sialic acid); CMP-sialic acid returns to the cytoplasm, where it is used by the Golgi as a substrate for sialyltransferases to enzymatically sialylate glycans (glycoproteins and glycolipids) (Fig. 1) [6, 7]. Alternatively, cytoplasmic CMP-sialic acid can feedback inhibit the UDP-GlcNAc 2-epimerase activity of GNE by binding to the enzyme’s allosteric site, creating a mechanism for controlling intracellular sialic acid production (Fig.…”

Section: Introductionmentioning

confidence: 99%

Safety, pharmacokinetics and sialic acid production after oral administration of N -acetylmannosamine (ManNAc) to subjects with GNE myopathy

Wang

Latham

et al. 2017

Molecular Genetics and Metabolism

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GNE myopathy is a rare, autosomal recessive, inborn error of sialic acid metabolism, caused by mutations in GNE, the gene encoding UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase. The disease manifests as an adult-onset myopathy characterized by progressive skeletal muscle weakness and atrophy. There is no medical therapy available for this debilitating disease. Hyposialylation of muscle glycoproteins likely contributes to the pathophysiology of this disease. N-acetyl-D-mannosamine (ManNAc), an uncharged monosaccharide and the first committed precursor in the sialic acid biosynthetic pathway, is a therapeutic candidate that prevents muscle weakness in the mouse model of GNE myopathy. We conducted a first-in-human, randomized, placebo-controlled, double-blind, single-ascending dose study to evaluate safety and pharmacokinetics of ManNAc in GNE myopathy subjects. Single doses of 3 and 6 g of oral ManNAc were safe and well tolerated; 10 g was associated with diarrhea likely due to unabsorbed ManNAc. Oral ManNAc was absorbed rapidly and exhibited a short half-life (~2.4 h). Following administration of a single dose of ManNAc, there was a significant and sustained increase in plasma free sialic acid (Neu5Ac) (Tmax of 8-11 h). Neu5Ac levels remained above baseline 48 h post-dose in subjects who received a dose of 6 or 10 g. Given that Neu5Ac is known to have a short half-life, the prolonged elevation of Neu5Ac after a single dose of ManNAc suggests that intracellular biosynthesis of sialic acid was restored in subjects with GNE myopathy, including those homozygous for mutations in the kinase domain. Simulated plasma concentration-time profiles support a dosing regimen of 6 g twice daily for future clinical trials.

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“…In functional terms, the presence of these substitutions can act as a molecular switch for the conformational behavior of the respective N-glycan and affect N-glycan binding to galectins ). The next epitopes monitored by plant/fungal lectins were sialylated N-glycans, produced by a family of sialyltransferases and involved in diverse intermolecular recognition processes (Bhide & Colley, 2017). The profiles of the N-glycan a2,3/6-sialylations showed clear quantitative differences, a2,3-sialylation being more frequent and abundant than a2,6-sialylation.…”

Section: Discussionmentioning

confidence: 99%

Network analysis of adhesion/growth‐regulatory galectins and their binding sites in adult chicken retina and choroid

et al. 2017

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The highly ordered multilayered organization of the adult chicken retina is a suitable test model for examining zonal distribution of the members of a bioeffector family. Based on the concept of the sugar code, the functional pairing of glycan epitopes with cognate receptors (lectins) is emerging as a means to explain the control of diverse physiological activities. Having recently completed the biochemical characterization of all seven adhesion/growth-regulatory galectins present in chicken, it was possible to establish how the individual characteristics of their expression profiles add up to shape the galectin network, which until now has not been defined at this level of complexity. This information will also have relevance in explaining the region-specific presence of glycan determinants in the retina, as illustrated in the first part of this study using a panel of nine plant/fungal agglutinins. The following systematic monitoring of the galectins yielded patterns for which quantitative and qualitative differences were detected. Obviously, positivity in distinct layers is not confined to a single protein of this family, e.g. CG-1A, CG-3 or CG-8. These results underline the requirement for network analysis for these proteins that can functionally interact in additive or antagonistic modes. Labeling of the tissue galectins facilitated profiling of their accessible binding sites. It also revealed differences among the galectin family members, highlighting the ability of this method to define binding properties on the level of tissue sections. Methodologically, the detection of endogenous lectins intimates that cognate glycans can become inaccessible, a notable caveat for lectin histochemical studies.

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Sialylation of N-glycans: mechanism, cellular compartmentalization and function

Cited by 182 publications

References 268 publications

ST3GAL3, ST3GAL4, and ST3GAL6 differ in their regulation of biological functions via the specificities for the α2,3‐sialylation of target proteins

ST3GAL3, ST3GAL4, and ST3GAL6 differ in their regulation of biological functions via the specificities for the α2,3‐sialylation of target proteins

Safety, pharmacokinetics and sialic acid production after oral administration of N -acetylmannosamine (ManNAc) to subjects with GNE myopathy

Network analysis of adhesion/growth‐regulatory galectins and their binding sites in adult chicken retina and choroid

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