1. Protein deglycation
Glucose spontaneously reacts with proteins, forming Schiff bases that spontaneously rearrange to Amadori products, also called fructosamines. A few years ago our group reported the identification of a mammalian enzyme, fructosamine 3-kinase, that phosphorylates the third carbon of fructosamines. This phosphorylation makes fructosamines unstable, causing them to detach from proteins, which are thus restored to their original state. Knocking out the fructosamine-3-kinase gene in mice leads to a significant increase in the amount of protein-bound fructosamines in the cytosol. A major problem we want now to focus on is why protein deglycation is important ? Are there proteins that are perturbed by glycation and does this have any significance with respect to diabetes, a disease in which protein glycation is enhanced due to the elevated glucose concentration.
Formation of fructosamines and their repair by fructosamine 3-kinase
Maybe even more intriguing than fructosamine 3-kinase is ‘fructosamine-3-kinase related protein’. This enzyme does not act on fructosamines, but it does phosphorylate other Amadori products : ribulosamines and erythrulosamines. Intriguingly, the tissue distribution of this enzyme is wider than that of FN3K; furthermore it is more active than the latter; finally the homologues of FN3K/FN3K-RP that are found in fishes, plants and bacteria also act on ribulosamines and erythrulosamines but never on fructosamines. This could mean that phosphorylation of ribulosamines and/or erythrulosamines is a more more important function than phosphorylation of fructosamines. Ribulosamines and erythrulosamines are most probably formed from ribose 5-phosphate and erythrose 4-phosphate, which are extremely potent glycating agents. We recently described that the enzyme named ‘low-molecular-weight protein-tyrosine-phosphatase’ (LMW-PTP) is better at converting ribulosamine-5-phosphates to ribulosamines than at dephosphorylating tyrosine-phosphates !
Formation of ribulosamine 5-phosphates and their repair by low-molecular weight-tyrosine phosphatase and FN3K-RP
Another potent glycating agent is glucose 6-phosphate. In tissues such as muscle, where the free glucose concentration is very low, the formation of fructosamines presumably mostly arises through the reaction of proteins with glucose 6-phosphate. The fructosamine 6-phosphates that are so formed are dephosphorylated by a phosphatase, MDP1, to become substrates of FN3K.
Establishing the role of these enzymes in protein repair, e.g, through the gene knockout approach, identifying their protein substrates and determining how protein function is altered in the absence of deglycation are our major goals.
To know more... (pdf chapter of the last de Duve Institute report)Publications >
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