Acetylation and glycosylation in protein folding and misfolding: Impact on ageing-related diseases GRK 2155 SP2

Glycosylation is the most abundant enzymatic posttranslational modification of proteins. Sialic acid represents the terminal monosaccharide of most glycoconjugates and is involved in a variety of cellular functions. Sialic acid is synthesized in the cytosol from UDP-N-acetylglucosamine (UDP-GlcNAc) by the UDP-GlcNAc-2-epimerase/ManNAc-kinase. UDP-GlcNAc-2-epimerase/ManNAc-kinase mutations cause hereditary inclusion body myopathy, a very serious age-related and late-onset disease of distal and proximal skeletal muscles. Recent studies have demonstrated that many intracellular proteins, which are normally non-glycosylated, are modified by a single O-linked GlcNAc on serine/threonine residues by the O-GlcNAc-transferase. O-GlcNAcylation influences the localization, activity or interaction of proteins. This is of special importance, since in age-dependent degenerating diseases, such as Alzheimer’s disease, false-regulated O-GlcNAcylation occurs. Several authors have suggested that both sialylation and O-GlcNAc modification of proteins correlate with ageing (espacially in neuronal, muscle and endothelial cells). Since both UDP-GlcNAc-2-epimerase/ManNAc-kinase and O-GlcNAc-transferase use UDP-GlcNAc as substrate, we assume that UDP-GlcNAc represents a novel age-dependent "metabolic sensor”. Since UDP-GlcNAc is synthesized from glcucose via fructose-6-phosphate, blood glucose concentration is heavely involved in the formation of the "metabolic sensor” UDP-GlcNAc.