UDP-GlcNAc 2-Epimerase/ManNAc Kinase (GNE): A Master Regulator of Sialic Acid Synthesis

Hinderlich, Stephan; Weidemann, Wenke; Yardeni, Tal; Horstkorte, Rüdiger; Huizing, Marjan

doi:10.1007/128_2013_464

Cited by 89 publications

(92 citation statements)

References 178 publications

(243 reference statements)

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“…The GNE gene encodes for UDP-N-acetylglucosamine 2epimerase/N-acetylmannosamine kinase (GNE), the bifunctional and rate-limiting enzyme in the biosynthesis of sialic acid [28,29] and a regulator of cell surface sialylation [30]. The GNE enzyme has an N-terminal epimerase enzymatic domain, containing the allosteric site for CMP-sialic acid feedback inhibition, and a C-terminal kinase enzymatic domain ( Fig.…”

Section: Gne Functionmentioning

confidence: 99%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic Brimmed^vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.

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Section: Gne Functionmentioning

confidence: 99%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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“…The biosynthesis of Neu5Ac is a highly regulated process and begins with the glycolysis product, fructose-6-phosphate, which is diverted to the synthesis of hexosamines by the enzyme glutamine fructose 6-phosphate amidotransferase (Hinderlich et al 2015;Varki and Schauer 2009). Following the acetylation of the free amine group of glucosamine-6-phosphate (GlcNH 2 -6-P) to form N-acetylglucosamine-6-phosphate (GlcNAc-6-P), an epimerization reaction converts GlcNAc-6-P to GlcNAc-1-phosphate (GlcNAc-1-P) which is then condensed with UTP to form UDP-GlcNAc.…”

Section: The Biosynthesis Of Sialic Acidsmentioning

confidence: 99%

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

Bhide

Colley

2016

Histochem Cell Biol

180

144

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Sialylated N-glycans play essential roles in the immune system, pathogen recognition and cancer. This review approaches the sialylation of N-glycans from three perspectives. The first section focuses on the sialyltransferases that add sialic acid to N-glycans. Included in the discussion is a description of these enzymes' glycan acceptors, conserved domain organization and sequences, molecular structure and catalytic mechanism. In addition, we discuss the protein interactions underlying the polysialylation of a select group of adhesion and signaling molecules. In the second section, the biosynthesis of sialic acid, CMP-sialic acid and sialylated N-glycans is discussed, with a special emphasis on the compartmentalization of these processes in the mammalian cell. The sequences and mechanisms maintaining the sialyltransferases and other glycosylation enzymes in the Golgi are also reviewed. In the final section, we have chosen to discuss processes in which sialylated glycans, both N- and O-linked, play a role. The first part of this section focuses on sialic acid-binding proteins including viral hemagglutinins, Siglecs and selectins. In the second half of this section, we comment on the role of sialylated N-glycans in cancer, including the roles of β1-integrin and Fas receptor N-glycan sialylation in cancer cell survival and drug resistance, and the role of these sialylated proteins and polysialic acid in cancer metastasis.

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“…A marked urinary excretion of free sialic acid is also observed in sialuria (Montreuil et al 1968), a nonlysosomal disease due to a defect in the GNE gene encoding uridine diphosphate-N-acetyl-D-glucosamine-2-epimerase, a key enzyme in sialic acid biosynthesis (Hinderlich et al 2015;C h e ne ta l . 2016).…”

Section: Free Sialic Acid Storage Disordersmentioning

confidence: 99%

Contribution of tandem mass spectrometry to the diagnosis of lysosomal storage disorders

Piraud

Pettazzoni

Lavoie

et al. 2018

J of Inher Metab Disea

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Tandem mass spectrometry (MS/MS) is a highly sensitive and specific technique. Thanks to the development of triple quadrupole analyzers, it is becoming more widely used in laboratories working in the field of inborn errors of metabolism. We review here the state of the art of this technique applied to the diagnosis of lysosomal storage disorders (LSDs) and how MS/MS has changed the diagnostic rationale in recent years. This fine technology brings more sensitive, specific, and reliable methods than the previous biochemical ones for the analysis of urinary glycosaminoglycans, oligosaccharides, and sialic acid. In sphingolipidoses, the quantification of urinary sphingolipids (globotriaosylceramide, sulfatides) is possible. The measurement of new plasmatic biomarkers such as oxysterols, bile acids, and lysosphingolipids allows the screening of many sphingolipidoses and related disorders (Niemann-Pick type C), replacing tedious biochemical techniques. Applied to amniotic fluid, a more reliable prenatal diagnosis or screening of LSDs is now available for fetuses presenting with antenatal manifestations. Applied to enzyme measurements, it allows high throughput assays for the screening of large populations, even newborn screening. The advent of this new method can modify the diagnostic rationale behind LSDs.

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UDP-GlcNAc 2-Epimerase/ManNAc Kinase (GNE): A Master Regulator of Sialic Acid Synthesis

Cited by 89 publications

References 178 publications

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

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

Contribution of tandem mass spectrometry to the diagnosis of lysosomal storage disorders

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