Biochemical and Biophysical Research Communications
Breakthroughs and ViewsO-GlcNAc: a regulatory post-translational modification
Section snippets
The enzymes
A soluble O-GlcNAc transferase (OGT) was first purified and characterized in 1990 [14] but it would be another seven years before the enzyme was cloned [8], [9]. The 110 kDa polypeptide has two domains: an N-terminus with 11.5 tetratricopeptide repeats (TPRs) and a putative catalytic C-terminus. TPRs are known protein–protein association domains [15]. The enzyme functions as a trimer with the polypeptide chains interacting via the TPRs [10]. The enzyme transfers N-acetylglucosamine from
Transcription/translation
A large number of transcription factors are modified by O-GlcNAc as well as the C-terminal domain (CTD) of RNA polymerase II [20]. Glycosylation of the CTD induces a conformational change in the CTD that could have a variety of functional consequences [21]. Recent data have shown that in vitro glycosylation of the CTD of RNA polymerase II prevents the required phosphorylation for elongation [22]. Thus it has been proposed that O-GlcNAc may modify RNA polymerase II that is in the preinitiation
Neurodegenration
There is considerable indirect evidence that O-GlcNAc may play a role in neurodegenerative disorders. It is well established that glucose metabolism is reduced in the aging neurons. A reduction in glucose flux results in lower UDP-GlcNAc levels and presumably lower levels of O-GlcNAc modified proteins. There are a variety of O-GlcNAc modified proteins that are enriched in brain neurons including tau, β-amyloid precursor protein, neurofilaments, microtubule-associated proteins, clathrin assembly
Signal transduction
While the attractive model of O-GlcNAc participating in signal transduction events has been proposed for more than a decade [41], only recently have data emerged implicating O-GlcNAc in specific signal transduction cascades. The hexosamine biosynthetic pathway (HSP), which converts fructose-6-phosphate to UDP-GlcNAc (see Fig. 1), the donor sugar nucleotide for OGT, has been implicated in type II diabetes, specifically in insulin resistance and glucose toxicity [43], [44]. Very compelling
Working model and future directions
The current nutritional sensor model of O-GlcNAc has been reviewed elsewhere [56]. Briefly, the model proposes that cells are not blindly responding to extracellular stimuli but instead are taking into account their own energy stores. O-GlcNAc, which appears to be highly responsive to nutrient state, modifies signaling components, cytoskeletal components, and the transcriptional and translational machinery. Thus, O-GlcNAc modification could be modulating the proteins that are present and their
Acknowledgements
We thank members of the Hart laboratory and Karen M. Wells for critical reading of the manuscript. The “O-GlcNAc field” is rapidly expanding and thus it is likely that we failed to acknowledge the contributions of some of our colleagues (for this we apologize). This work was supported by NIH Grants CA42486, DK38418, and HD13563 to GWH.
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