Receptor-mediated endocytic uptake of methylglyoxal-modified serum albumin. Competition with advanced glycation end product-modified serum albumin at the advanced glycation end product receptor.
Methylglyoxal binds and irreversibly modifies arginine and lysine residues in bovine serum albumin (BSA) under physiological conditions, producing a protein with an increased net negative charge at physiological pH. At 4 degrees C, methylglyoxal-modified BSA (MG-BSA) was bound by cell surface receptors on murine P388D1 macrophages. The apparent dissociation constant KD value was 435 +/- 2 nM, and there were 8.89 +/- 0.02 x 10(5) receptors/cell (n = 6), compare with an apparent KD value of 263 +/- 52 nM and 10.17 +/- 0.93 x 10(5) receptors/cell (n = 11) for advanced glycation end product-modified BSA (AGE-BSA). AGE-BSA competed with MG-BSA for binding to a common receptor; however, a component of AGE-BSA receptor binding could not be displaced by MG-BSA, and a component of MG-BSA receptor binding could not be displaced by AGE-BSA, suggesting that there are binding sites for both AGE-BSA and MG-BSA, competitive and noncompetitive, to MG-BSA and AGE-BSA on P388D1 cells at 4 degrees C. At 37 degrees C, receptor binding of AGE-BSA and MG-BSA was followed by endocytosis and lysosomal degradation of the modified protein. Methylglyoxal-modified proteins are ligands for the AGE receptor, and their formation and metabolism may be linked to the development of diabetic complications.
Westwood
M E
ME
Department of Chemistry and Biological Chemistry, University of Essex, Colchester, United Kingdom.
McLellan
A C
AC
Thornalley
P J
PJ
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D004705:Endocytosis; D005947:Glucose / Q000737:chemistry; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D011765:Pyruvaldehyde / Q000737:chemistry*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012710:Serum Albumin, Bovine; D011765:Pyruvaldehyde; D005947:Glucose