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Peptide Mapping of Human Serum Albumin Modified Minimally by Methylglyoxal in Vitro and in Vivo
Department of Biological Sciences, University of Essex, Colchester, UK
Address for correspondence: Paul J. Thornalley, Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK. Voice: 44-1206-873010; fax: 44-1206-873010. thorp{at}essex.ac.uk
Methylglyoxal is a potent glycating agent and important precursor of advanced glycation end products (AGEs) in physiological systems. Unlike glucose, methylglyoxal is predominantly an arginine-directed glycating agent. Methylglyoxal reacts with proteins to form mainly the arginine-derived hydroimidazolone AGE, N
 -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), argpyrimidine, the lysine-derived AGEs, N -(1-carboxyethyl)lysine (CEL), and methylglyoxal-derived lysine dimer (MOLD). Sites within proteins susceptible to modification by methylglyoxal have not been identified. Here we show that modification of human serum albumin by methylglyoxal forms mainly hydroimidazolone MG-H1 residues. The location of MG-H1 residues was identified by mass spectrometric peptide mapping. This method identified a hot spot of hydroimidazolone formation at Arg-410, with other minor MG-H1 modifications at Arg-114, Arg-186, Arg-218, and Arg-428. Other extracellular and intracellular proteins are modified by methylglyoxal in physiological systems. Modification of arginine residues by methylglyoxal may be particularly damaging because arginine residues have a high frequency of occurrence in ligand and substrate recognition sites in receptor and enzyme active sites.
Key Words: glycation • methylglyoxal • albumin • drug binding • peptide mapping
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