Unusual susceptibility of heme proteins to damage by glucose during non-enzymatic glycation.
Glucose modifies the amino groups of proteins by a process of non-enzymatic glycation, leading to potentially deleterious effects on structure and function that have been implicated in the pathogenesis of diabetic complications. These changes are extremely complex and occur very slowly. We demonstrate here that hemoglobin and myoglobin are extremely susceptible to damage by glucose in vitro through a process that leads to complete destruction of the essential heme group. This process appears in addition to the expected formation of so-called advanced glycation end products (AGEs) on lysine and other side-chains. AGE formation is enhanced by the iron released. In contrast, the heme group is not destroyed during glycation of cytochrome c, where the sixth coordination position of the heme iron is not accessible to solvent ligands. Glycation leads to reduction of ferricytochrome c in this case. Since hydrogen peroxide is known to destroy heme, and the destruction observed during glycation of hemoglobin and myoglobin is sensitive to catalase, we propose that the degradation process is initiated by hydrogen peroxide formation. Damage may then occur through reaction with superoxide generated (a reductant of ferricytochrome c), or hydroxyl radicals, or with both.
D000818:Animals; D002417:Cattle; D005609:Free Radicals / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000096:biosynthesis*; D006031:Glycosylation; D006420:Hemeproteins / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006736:Horses; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D009211:Myoglobin / Q000378:metabolism; D010084:Oxidation-Reduction; D013057:Spectrum Analysis
D005609:Free Radicals; D017127:Glycation End Products, Advanced; D006420:Hemeproteins; D006454:Hemoglobins; D009211:Myoglobin; D006861:Hydrogen Peroxide; D007501:Iron; D005947:Glucose