Protein Aging by Carboxymethylation of Lysines Generates Sites for Divalent Metal and Redox Active Copper Binding: Relevance to Diseases of Glycoxidative Stress

Author： Saxena A.K. Saxena P. Wu X. Obrenovich M. Weiss M.F. Monnier V.M.

Publisher： Elsevier

ISSN： 0006-291X

Source： Biochemical and Biophysical Research Communications, Vol.260, Iss.2, 1999-07, pp. : 332-338

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Abstract

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^ε-(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 Cu²⁺, Zn²⁺ and Ca²⁺. CML-BSA-copper complexes oxidized ascorbate and depolymerized protein in the presence of H₂O₂. 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 H₂O₂. 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.