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Aberrant O-GlcNAcylation disrupts GNE enzyme activity in GNE myopathy. | LitMetric

AI Article Synopsis

  • GNE is the main enzyme involved in producing sialic acids, crucial for cell interactions and related to various diseases.
  • A mutation in GNE decreases its activity by 30% and is linked to a severe form of muscle disease called GNE myopathy.
  • The study reveals that a specific mutation (M743T) increases a modification called O-GlcNAcylation, which improves enzyme activity and stability compared to the normal GNE.

Article 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.

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Source
http://dx.doi.org/10.1111/febs.13729DOI Listing

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