Copper catalyzed oxidation of Alzheimer Abeta.
Abeta derived from amyloid plaques of Alzheimer's disease-affected brain contain several oxidative posttranslational modifications. In this study we have characterized the amino acid content of human amyloid-derived Abeta and compared it with that of human synthetic Abeta subjected to metal-catalyzed oxidation. Human amyloid derived Abeta has an increased content of arginine (46%) and glutamate/glutamine residues (28%), but a decreased content of histidine residues (-32%) as compared to the expected amino acid content. Incubation of synthetic human Abeta with Cu(II), but not Fe(III), in the presence of H2O2 similarly induced a decrease in histidine residues (-79%), but also a decrease in tyrosine residues (-28%). Our results suggest that histidine and tyrosine are most vulnerable to metal mediated oxidative attack, consistent with our earlier findings that Cu coordinated via histidine residues is redox competent. Our results suggest that the loss of histidine residues in human amyloid-derived Abeta may be a result of Cu oxidation, and that unidentified post-translational mechanisms operate to modify other amino acids of Abeta in vivo.
Atwood
C S
CS
Massachusetts General Hospital East, Charlestown, MA 02129-9142, USA.
Huang
X
X
Khatri
A
A
Scarpa
R C
RC
Kim
Y S
YS
Moir
R D
RD
Tanzi
R E
RE
Roher
A E
AE
Bush
A I
AI
D000544:Alzheimer Disease / Q000378:metabolism*; D000596:Amino Acids / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001120:Arginine / Q000737:chemistry; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry
D000596:Amino Acids; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005973:Glutamine; D018698:Glutamic Acid; D014443:Tyrosine; D006639:Histidine; D003300:Copper; D001120:Arginine; D006861:Hydrogen Peroxide; D007501:Iron; D010100:Oxygen