A post-Amadori inhibitor
pyridoxamine also inhibits chemical modification of proteins by
scavenging carbonyl intermediates of carbohydrate and lipid degradation.
Voziyan PA, Metz TO, Baynes JW,
Hudson BG.
Department of Biochemistry and Molecular
Biology
University of Kansas Medical Center
Kansas City, KS. 66160 pvoziyan@kumc.edu
J Biol Chem. 2002 Feb 1;277(5):3397-403. Epub 2001 Nov 29
Abstract
Reactive carbonyl compounds are
formed during autoxidation of carbohydrates and peroxidation of lipids.
These compounds are intermediates in the formation of advanced glycation
end products (AGE) and advanced lipoxidation end products (ALE) in
tissue proteins during aging and in chronic disease. We studied the
reaction of carbonyl compounds glyoxal (GO) and glycolaldehyde (GLA)
with pyridoxamine, a potent post-Amadori inhibitor of AGE formation in
vitro and of development of renal and retinal pathology in diabetic
animals. Pyridoxamine reacted rapidly with GO and GLA in neutral,
aqueous buffer, forming a Schiff base intermediate that cyclized to a
hemiaminal adduct by intramolecular reaction with the phenolic hydroxyl
group of pyridoxamine. This bicyclic intermediate dimerized to form a
five-ring compound with a central piperazine ring, which was
characterized by electrospray ionization-liquid chromatography/mass
spectrometry, NMR, and x-ray crystallography. Pyridoxamine also
inhibited the modification of lysine residues and loss of enzymatic
activity of RNase in the presence of GO and GLA and inhibited formation
of the AGE/ALE N(epsilon)-(carboxymethyl)lysine during reaction of GO
and GLA with bovine serum albumin. Our data suggest that the AGE/ALE
inhibitory activity and the therapeutic effects of pyridoxamine observed
in diabetic animal models depend, at least in part, on its ability to
trap reactive carbonyl intermediates in AGE/ALE formation, thereby
inhibiting the chemical modification of tissue proteins.
