The role of O-linked protein glycosylation in β-cell dysfunction

RJ Konrad, JE Kudlow - International journal of …, 2002 - spandidos-publications.com
RJ Konrad, JE Kudlow
International journal of molecular medicine, 2002spandidos-publications.com
Although only recently described, the pathway of O-linked protein glycosylation is already
being implicated in diseases as diverse as cancer and Alzheimer's. Unlike the better known
N-linked pathway, O-linked protein glycosylation is a dynamic and regulated event, much
like tyrosine phosphorylation. During the process of O-glycosylation, the enzyme O-GlcNAc
transferase (OGT) uses the substrate UDP-N-acetylglucosamine (UDP-GlcNAc) to attach a
single O-linked N-acetylglucosamine (O-GlcNAc) to nuclear and cytosolic proteins on serine …
Abstract
Although only recently described, the pathway of O-linked protein glycosylation is already being implicated in diseases as diverse as cancer and Alzheimer's. Unlike the better known N-linked pathway, O-linked protein glycosylation is a dynamic and regulated event, much like tyrosine phosphorylation. During the process of O-glycosylation, the enzyme O-GlcNAc transferase (OGT) uses the substrate UDP-N-acetylglucosamine (UDP-GlcNAc) to attach a single O-linked N-acetylglucosamine (O-GlcNAc) to nuclear and cytosolic proteins on serine or threonine residues. Conversely, the enzyme O-GlcNAc-selective N-acetyl-β-D-glucosaminidase (O-GlcNAcase) removes the O-GlcNAc, returning the protein to its baseline state until the cycle repeats itself. Although proving to be of interest in many different tissues, this pathway is especially important in pancreatic β-cells. The β-cell is unique in containing much more OGT than any other cell type. This enables β-cells to respond to physiological increases in the glucose concentration by converting glucose to the OGT substrate UDP-GlcNAc, thereby dynamically coupling intra-cellular O-linked protein glycosylation to the extracellular glucose concentration. As a result, the β-cell also appears to be especially susceptible to disruption of the O-glycosylation pathway. The diabetogenic agent streptozotocin (STZ), a UDP-GlcNAc analogue, causes β-cell toxicity by irreversibly inhibiting O-GlcNAcase, while the diabetogenic agent alloxan (ALX), also a UDP-GlcNAc analog irreversibly inhibits OGT. This review will summarize what is currently known about β-cell O-glycosylation and expand upon historical observations of chemically-induced β-cell toxicity in animals to develop a model suggesting how β-cell O-glycosylation is also involved in the development and progession of type 2 diabetes in humans.
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