Fructoselysine 3-phosphate is synthesized in vivo by the recently discovered fructoseamine-3-kinase (F3K) from fructoselysine and ATP and decomposes to lysine, Pi and 3-deoxyglucosone (3DG). This pathway appears to dominate 3DG production in vivo, making it possible to modulate 3DG levels by stimulating or inhibiting the reaction. Present inhibitors are non-reacting substrate analogues with relatively high Ki values and can inhibit F3K sufficiently in vivo to reduce 3DG in diabetic rat plasma by approx. 50%. Stimulation of the F3K pathway by feeding glycated casein causes an increase of 10–20-fold in plasma levels of 3DG and 3-fold in kidney tubules. Consequences of this increase were studied in two systems: the Eker rat, a model of susceptible kidney tubules; and birth rates in two rat strains. In both cases substantial pathological effects were observed. In the Eker rats, an approx. 3-fold increase in kidney lesions was observed (P<0.00001). In both Fischer 344 and Sprague–Dawley rats, birth rates were reduced by 56% (P<0.0001) and 12% (P<0.015) respectively. These results suggest that inhibition of F3K is a promising new therapeutic target for diabetic complications, as well as other 3DG-dependent pathologies.
Conference Article| December 01 2003
Modulation of in vivo 3-deoxyglucosone levels
Biochem Soc Trans (2003) 31 (6): 1433–1437.
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T.R. Brown, B. Su, K.A. Brown, M.A. Schwartz, A.M. Tobia, F. Kappler; Modulation of in vivo 3-deoxyglucosone levels. Biochem Soc Trans 1 December 2003; 31 (6): 1433–1437. doi: https://doi.org/10.1042/bst0311433
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