Protein aging by carboxymethylation of lysines generates sites for divalent metal and redox active copper binding: relevance to diseases of glycoxidative stress.
Aging and age-related diseases are associated with the production of reactive oxygen species which modify lipids, proteins and DNA. Here we hypothesized the glyco- and lipoxidation product N(epsilon)-(carboxymethyl)lysine (CML) in proteins should bind divalent and redox active transition metal binding. CML-rich poly-L-lysine and bovine serum albumin (BSA) were chemically prepared and found to bind non-dialyzable Cu(2+), Zn(2+) and Ca(2+). CML-BSA-copper complexes oxidized ascorbate and depolymerized protein in the presence of H(2)O(2). CML-rich tail tendons implanted for 25 days into the peritoneal cavity of diabetic rats had a 150% increase in copper content and oxidized ascorbate three times faster than controls. CML-rich proteins immunoprecipitated from serum of uremic patients oxidized four times more ascorbate than control and generated spin adducts of DMPO in the presence of H(2)O(2). The chelator DTPA suppressed ascorbate oxidation thereby implicating transition metals in the process. In aging and disease, CML accumulation may result in a deleterious vicious cycle since CML formation itself is catalyzed by lipoxidation and glycoxidation.
Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106, USA.
A K
AK
Saxena
P
P
Saxena
X
X
Wu
M
M
Obrenovich
M F
MF
Weiss
V M
VM
Monnier
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D001665:Binding Sites; D001704:Biopolymers; D002384:Catalysis; D002413:Cations, Divalent; D003094:Collagen / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005609:Free Radicals; D017127:Glycation End Products, Advanced; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008745:Methylation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism
D001704:Biopolymers; D002413:Cations, Divalent; D005609:Free Radicals; D017127:Glycation End Products, Advanced; D012694:Serine; C048496:N(6)-carboxymethyllysine; D003300:Copper; D003094:Collagen; D006861:Hydrogen Peroxide; D009195:Peroxidase; D008239:Lysine; D001205:Ascorbic Acid