Modulation of in vivo 3-deoxyglucosone levels. (1st December 2003)

• Record Type: Journal Article
• Authors: Brown, T.R.; Su, B.; Brown, K.A.; Schwartz, M.A.; Tobia, A.M.; Kappler, F.
• Is Part Of: Biochemical Society transactions. Volume 31:Number 6(2003)
• Page Start: 1433
• Page End: 1437
• Publication Date: 2003-12-01
• Subjects: 3-deoxyglucosone -- glycation; Biochemistry -- Congresses; 572
• DOI: 10.1042/bst0311433
• Languages: English
• ISSNs: 0300-5127

Abstract

Abstract : 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 K i 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.