Premium
Pyridoxamine (PM) protects proteins from functional damage by 3‐deoxyglucosone (3DG)
Author(s) -
Chetyrkin Sergei,
Zhang W,
Serianni Anthony S,
Hudson Billy G,
Voziyan Paul A
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a294-b
Subject(s) - chemistry , rnase p , lysozyme , incubation , diabetic nephropathy , cell adhesion , biochemistry , pharmacology , cell , endocrinology , biology , kidney , rna , gene
3DG is a reactive dicarbonyl compound elevated in diabetic tissues and implicated in the development of diabetic complications. We have evaluated the effects of 3DG on activity of model enzymes, RNase and lysozyme, and on the ability of collagen IV to support the adhesion of glomerular mesangial cells. After 30 days of incubation at 37°C in the presence of 5 mM 3DG, RNase activity was inhibited by 40% and lysozyme activity was inhibited by 95%. Collagen IV was incubated with 1 mM 3DG at 37°C for 60 days followed by the complete removal of 3DG and determination of cell adhesion. Treatment with 3DG resulted in over 70% inhibition of mesangial cell adhesion. Recent clinical trials have identified PM as a promising drug candidate for treatment of diabetic nephropathy. However, the mechanism of PM action in vivo is unknown. One possibility is that PM scavenges toxic carbonyl compounds such as 3DG. PM protected both RNase and lysozyme activity from inhibition by 3DG. PM also protected the ability of collagen IV to support mesangial cell adhesion. We investigated the mechanism of PM protection from the loss of protein function caused by 3DG. The PM amino group was consumed in the presence of 3DG, indicating possible adduct formation. The RP‐HPLC analysis of the incubation mixture revealed the appearance of a new peak. When the incubation mixture was analyzed by positive‐mode ESI‐MS, a new compound with m/z 313 was identified, consistent with the formation of 3DG‐PM adduct. We conclude that 3DG can cause functional damage to enzymes and matrix proteins. The ability of PM to protect proteins from 3DG‐induced damage may underlie, in part, its therapeutic effects in diabetic nephropathy.