Paradoxical impact of ntioxidants on post-amadori glycoxidation : counterintuitive increase in the yields of pentosidine and n{epsilon}-carboxymethyllysine using a novel multifunctional pyridoxamine derivative

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DOIResolve DOI: http://doi.org/10.1074/jbc.M305099200
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TypeArticle
Journal titleThe Journal Of Biological Chemistry
Volume278
Issue40
Pages3838438394; # of pages: 11
AbstractThe inhibition of post-Amadori advanced glycation end product (AGE) formation by three different classes of AGE inhibitors, carbonyl group traps, chelators, and radical-trapping antioxidants, challenge the current paradigms that: 1) AGE inhibitors will not increase the formation of any AGE product, 2) transition metal ions are required for oxidative formation of AGE, and 3) screening AGE inhibitors only in systems containing transition metal ions represents a valid estimate of potential in vivo mechanisms. This work also introduces a novel multifunctional AGE inhibitor, 6-dimethylaminopyridoxamine (dmaPM), designed to function as a combined carbonyl trap, metal ion chelator, and radical-trapping antioxidant. Other AGE inhibitors including pyridoxamine, aminoguanidine, o-phenylenediamine, dipyridoxylamine, and diethylenetriaminepentaacetic acid were also examined. The results during uninterrupted and interrupted ribose glycations show: 1) an unexpected increase in the yield of pentosidine in the presence of radical-trapping phenolic antioxidants such as Trolox and dmaPM, 2) significant formation of N{epsilon}-carboxymethyllysine (CML) in the presence of strong chelators and phenolic antioxidants, which implies that there must be nonradical routes to CML, 3) prevention of intermolecular cross-links with radical-trapping inhibitors, and 4) that dmaPM shows excellent inhibition of AGE. Glucose glycations reveal the expected inhibition of pentosidine and CML with all compounds tested, but in a buffer free of trace metal ions the yield of CML in the presence of radical-trapping antioxidants was between the metal ion-free and metal ion-containing controls. Protein molecular weight analyses support the conclusion that Amadori decomposition pathways are constrained in the presence of metal ion chelators and radical traps.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada; NRC Steacie Institute for Molecular Sciences; NRC Institute for Biological Sciences
Peer reviewedNo
NPARC number12328702
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Record identifier11571cdc-d1ad-4def-876d-5e13a51db5b6
Record created2009-09-10
Record modified2016-05-09
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