Methylglyoxal-modified arginine residues--a signal for receptor-mediated endocytosis and degradation of proteins by monocytic THP-1 cells.


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.

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@article{Westwood1997MethylglyoxalmodifiedAR, title={Methylglyoxal-modified arginine residues--a signal for receptor-mediated endocytosis and degradation of proteins by monocytic THP-1 cells.}, author={Marie E Westwood and Ognyan K. Argirov and E A Abordo and Paul J. Thornalley}, journal={Biochimica et biophysica acta}, year={1997}, volume={1356 1}, pages={84-94} }