title: Methylglyoxal-modified arginine residues--a signal for receptor-mediated endocytosis and degradation of proteins by monocytic THP-1 cells.
abstract: Non-enzymatic glycosylation or glycation of proteins to form advanced glycation endproducts (AGE) has been proposed as a process which provides a signal for the degradation of proteins. Despite this, the AGE which act a recognition factor for receptor-mediated endocytosis and degradation of glycated proteins by monocytes and macrophages has not been identified. Methylglyoxal, a reactive alpha-oxoaldehyde and physiological metabolite, reacted irreversibly with arginine residues in proteins to form Ndelta-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine and Ndelta-(5-methyl-4-imidazolon-2-yl)ornithine residues. Human serum albumin minimally-modified with methylglyoxal (MG(min)-HSA) was bound by cell surface receptors of human monocytic THP-1 cells in vitro at 4 degrees C: the binding constant K(d) value was 377 +/- 35 nM and the number of receptors per cell was 5.9 +/- 0.2 X 10(5) (n = 12). N alpha-Acetyl-Ndelta-(5-hydro-5-methyl-4-imidazolon-2-yl)orni thine displaced MG(min)-HSA from THP-1 cells, suggesting that the Ndelta-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine residue was the receptor recognition factor. At 37 degrees C, MG(min)-HSA was internalised by THP-1 cells and degraded. Similar binding and degradation of human serum albumin modified by glucose-derived AGE was found but only when highly modified. MG(min)-HSA, therefore, is the first example of a protein minimally-modified by AGE-like compounds that binds specifically to monocyte receptors. The irreversible modification of proteins by methylglyoxal is a potent signal for the degradation of proteins by monocytic cells in which the arginine derivative, Ndelta-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine, is the receptor recognition factor. This factor is not present in glucose-modified proteins.
authors.affiliation: Department of Biological and Chemical Sciences, University of Essex, Colchester, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Westwood
authors.forename: O K
authors.initials: OK
authors.lastname: Argirov
authors.forename: E A
authors.initials: EA
authors.lastname: Abordo
authors.forename: P J
authors.initials: PJ
authors.lastname: Thornalley
mesh_terms: D001120:Arginine / Q000737:chemistry; D001667:Binding, Competitive; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry*; D011516:Prothrombin / Q000737:chemistry / Q000378:metabolism; D011765:Pyruvaldehyde / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D013696:Temperature; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D012709:Serum Albumin; D011765:Pyruvaldehyde; D011516:Prothrombin; D001120:Arginine