DYN 12, a small molecule inhibitor of the enzyme amadorase, lowers plasma 3-deoxyglucosone levels in diabetic rats.
3-Deoxyglucosone (3DG) is a highly reactive alpha-dicarbonyl sugar and potent protein cross-linker that is important in the formation of advanced glycation end products (AGEs), which have been postulated to lead to the development of diabetic complications. (1) Reducing 3DG levels in diabetics is a potentially effective therapy to slow the development of diabetic complications. Standard biochemical methods were used to isolate, identify, and characterize the enzyme responsible for the production of 3DG, in order to develop an effective therapeutic agent against this target. We have purified and characterized Amadorase, a fructosamine-3-kinase, and demonstrated both in vitro and in vivo that it is responsible for the production of 3-deoxyglucosone (3DG). A small molecule inhibitor of Amadorase, DYN 12, significantly lowered plasma levels of 3DG in diabetic (by 46%, p = 0.0116) and normal (by 43%, p = 0.0024) rats. These data are the first indications that it is possible to significantly reduce 3DG production in diabetics and thus possibly reduce the development of diabetic complications.
Kappler
F
F
The Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Schwartz
M L
ML
Su
B
B
Tobia
A M
AM
Brown
T
T
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000097:blood*; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000097:blood* / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000473:pathology; D009930:Organic Chemicals; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D051381:Rats; D012016:Reference Values
C453542:DYN 12; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D009930:Organic Chemicals; D003847:Deoxyglucose; D000594:Amino Acid Oxidoreductases; C103012:amadoriase; D017853:Phosphotransferases (Alcohol Group Acceptor); C414347:fructosamine-3-kinase; C016350:3-deoxyglucosone