Increased protein glycation in fructosamine 3-kinase-deficient mice

Veiga da Cunha, Maria [UCL] Jacquemin, Patrick [UCL] Delpierre, Ghislain [UCL] Godfraind, Catherine [UCL] Théate, Ivan [UCL] Vertommen, Didier [UCL] Clotman, Frédéric [UCL] Lemaigre, Frédéric [UCL] Devuyst, Olivier [UCL] Van Schaftingen, Emile [UCL]

Amines, including those present on proteins, spontaneously react with glucose to form fructosamines in a reaction known as glycation. In the present paper, we have explored, through a targeted gene inactivation approach, the role of FN3K (fructosamine 3-kinase), an intracellular enzyme that phosphorylates free and protein-bound fructose-epsilon-lysines and which is potentially involved in protein repair. Fn3k-/- mice looked healthy and had normal blood glucose and serum fructosamine levels. However, their level of haemoglobin-bound fructosamines was approx. 2.5-fold higher than that of control (Fn3k+/+) or Fn3k+/- mice. Other intracellular proteins were also significantly more glycated in Fn3k-/- mice in erythrocytes (1.8-2.2-fold) and in brain, kidney, liver and skeletal muscle (1.2-1.8-fold), indicating that FN3K removes fructosamines from intracellular proteins in vivo. The urinary excretion of free fructose-epsilon-lysine was 10-20-fold higher in fed mice compared with mice starved for 36 h, and did not differ between fed Fn3k+/+ and Fn3k-/- mice, indicating that food is the main source of urinary fructose-epsilon-lysine in these mice and that FN3K does not participate in the metabolism of food-derived fructose-epsilon-lysine. However, in starved animals, the urinary excretion of fructose-epsilon-lysine was 2.5-fold higher in Fn3k-/- mice compared with Fn3k+/+ or Fn3k+/- mice. Furthermore, a marked increase (5-13-fold) was observed in the concentration of free fructose-epsilon-lysine in tissues of fed Fn3k-/- mice compared with control mice, indicating that FN3K participates in the metabolism of endogenously produced fructose-epsilon-lysine. Taken together, these data indicate that FN3K serves as a protein repair enzyme and also in the metabolism of endogenously produced free fructose-epsilon-lysine.