Transglycation--a potential new mechanism for deglycation of Schiff's bases.
Nonenzymatic glycation is believed to play a major role in the development of diabetic complications. Over the past several years we and others have shown that in cells this nonenzymatic process can be reversed by an ATP-dependent reaction catalyzed by fructosamine-3-kinase (FN3K) and possibly by its isozyme, fructosamine-3-kinase-related protein (FN3KRP). In this study we provide the first evidence that this FN3K-dependent deglycation, acting on the Amadori products, is complemented by another deglycation process operating on the very first product of nonenzymatic glycation, glucosylamines (Schiff's bases). We postulate that the first step in this Schiff's-base deglycation process occurs by transfer of the sugar moiety from macromolecule-bound glucosylamine to one of the low-molecular weight intracellular nucleophiles-in particular, glutathione. We term this reaction transglycation, and in this study we demonstrate that it occurs readily and spontaneously in vitro. We further propose that one of the spontaneously formed glucose-glutathione adduct(s) is subsequently removed from cells by a multidrug-resistance pump (MRP, MDR-protein, ATP-binding-cassette protein), metabolized, and excreted in urine. In support of this latter contention, we show that at least one transglycation product, glucose-cysteine, is found in human urine and that its concentrations are increased in diabetes.
Szwergold
Benjamin S
BS
Dartmouth Medical School, Remsen 311-314, HB 7515, Hanover, NH 03755, USA. Szwergold@Dartmouth.edu
Howell
Scott K
SK
Beisswenger
Paul J
PJ
D004912:Erythrocytes / Q000201:enzymology; D005947:Glucose; D005978:Glutathione / Q000097:blood; D006442:Glycated Hemoglobin / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008239:Lysine; D008954:Models, Biological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D012545:Schiff Bases
D005947:Glucose; D005978:Glutathione; D006442:Glycated Hemoglobin; D008239:Lysine; D017853:Phosphotransferases (Alcohol Group Acceptor); D012545:Schiff Bases; C479999:FN3KRP protein, human; C414347:fructosamine-3-kinase