Biochemical characterization of human and murine isoforms of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE)

Institute of Biochemistry and Molecular Biology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Arnimallee 22, 14195, Berlin-Dahlem, Germany.
Glycoconjugate Journal (Impact Factor: 2.52). 10/2008; 26(4):415-22. DOI: 10.1007/s10719-008-9189-6
Source: PubMed


The bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is the key enzyme for the biosynthesis of sialic acids, terminal components of glycoconjugates associated with a variety of physiological and pathological processes. Different protein isoforms of human and mouse GNE, deriving from splice variants, were predicted recently: GNE1 represents the GNE protein described in several studies before, GNE2 and GNE3 are proteins with extended and deleted N-termini, respectively. hGNE2, recombinantly expressed in insect and mamalian cells, displayed selective reduction of UDP-GlcNAc 2-epimerase activity by the loss of its tetrameric state, which is essential for full enzyme activity. hGNE3, which had to be expressed in Escherichia coli, only possessed kinase activity, whereas mGNE1 and mGNE2 showed no significant differences. Our data therefore suggest a role of GNE1 in basic supply of cells with sialic acids, whereas GNE2 and GNE3 may have a function in fine-tuning of the sialic acid pathway.

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Available from: Stefan O Reinke, Mar 09, 2015
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    • "UDP-GlcNAc2-epimerase catalyzes the rate-limiting step in sialic acid biosynthesis and MNK catalyzes the subsequent step. Sialic acids, which are N-acetylated derivatives of neuraminic acid, are the most abundant terminal monosaccharides on the glycoconjugates of eukaryotic cell surfaces, and they play important roles in development, regeneration, and biomedical functioning.2,3 "
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    ABSTRACT: GNE myopathy is characterized by early-adult-onset distal myopathy sparing quadriceps caused by mutations in the GNE gene encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, an enzyme in the sialic-acid synthesis pathway. A 27-year-old Korean woman presented a rapid deterioration in strength of the distal lower limbs during her first pregnancy. She was diagnosed with GNE myopathy and carrying the compound heterozygous mutations of the GNE gene (D208N/M29T). This is a representative case implying that an increased requirement of sialic acid during pregnancy might trigger a clinical worsening of GNE myopathy.
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    • "Novel protein isoforms of human GNE were predicted from the two splice variants including exon A1 (Reinke and Hinderlich, 2007). Consequently, human GNE exist in three different isoforms, namely hGNE1, hGNE2, and hGNE3 (Reinke et al., 2009). hGNE2 and hGNE3 possess extended and deleted N-termini, respectively (Figure 3). "
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    ABSTRACT: The key enzyme for the biosynthesis of N-acetylneuraminic acid, from which all other sialic acids are formed, is the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). GNE is a highly conserved protein found throughout the animal kingdom. Its highest expression is seen in the liver and placenta. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac, which is defect in the human disease sialuria. GNE knock-out in mice leads to embryonic lethality, emphasizing the crucial role of this key enzyme for sialic acid biosynthesis. The metabolic capacity to synthesize sialic acid and CMP-sialic acid upon ManNAc loads is amazingly high. An additional characteristic of GNE is its interaction with proteins involved in the regulation of development, which might play a crucial role in the hereditary inclusion body myopathy. Due to the importance of increased concentrations of tumor-surface sialic acid, first attempts to find inhibitors of GNE have been successful.
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