title: Aberrant O-GlcNAcylation disrupts GNE enzyme activity in GNE myopathy.
abstract: UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is the key enzyme for the biosynthesis of sialic acids. Sialic acids are terminal monosaccharides of glycoconjugates and gangliosides, which have an essential influence on various cell interactions. The sialylation of proteins varies during development, aging, and pathogenesis of degenerative diseases such as Morbus Alzheimer, diabetes mellitus type II, or myopathies. Mutation of methionine 743 in the GNE leads to a 30% reduction of the enzyme activity and is responsible for an aggressive form of GNE myopathy. GNE myopathy or hereditary inclusion body myopathy (HIBM) is an age-dependent muscular dystrophy. Here, we analyzed the impact of the exchange of methionine to threonine at position 743 which introduces an additional potential phosphorylation/O-GlcNAcylation site. We found increased O-GlcNAcylation of the M743T variant compared to the wild-type GNE. In addition, removal of the O-GlcNAc of the M743T variant resulted in an increased activity comparable to activity of the wild-type GNE. Furthermore, the half-life of the M743T variant is two times longer than for the wild-type GNE protein. This study provides that the balance of phosphorylation and O-GlcNAcylation is decisive involved in efficiency and regulation of GNE.
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Dorit
authors.initials: D
authors.lastname: Bennmann
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Wenke
authors.initials: W
authors.lastname: Weidemann
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Thate
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Kreuzmann
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Horstkorte
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000215:Acylation / Q000235:genetics; D049310:Distal Myopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008715:Methionine / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D012794:Sialic Acids / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009097:Multienzyme Complexes; D012794:Sialic Acids; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D008715:Methionine; D000117:Acetylglucosamine
keywords: GNE; GNE myopathy; O-GlcNAcylation; epimerase activity; half-life time of GNE