title: Heme-Cu bound aβ peptides: spectroscopic characterization, reactivity, and relevance to Alzheimer's disease.
abstract: Recently, it has been shown that heme binds to Aβ peptides which may play a major role in Alzheimer's disease (AD). This study illustrates that Aβ peptides can bind both Cu and heme cofactors at the same time. Both cofactors have unique spectroscopic and electrochemical features which are unaffected in the presence of the other, implying that they are electronically, chemically, and electrochemically uncoupled. These data clearly indicate that Cu cannot bind to three histidine residues simultaneously in Cu-Aβ complexes as previously proposed, since one of the histidines is involved in binding heme. The heme-Aβ and the heme-Cu-Aβ peptide complexes function as peroxidases. Interestingly, the Cu-Aβ complex also exhibits peroxidase activity, which may have significant implications in AD. Both Cu(+)-Aβ and heme (Fe(2+))-Aβ complexes reduce O(2) to H(2)O(2) quantitatively. Only one of the two electrons that are required for the reduction of O(2) to H(2)O(2) is derived from the reduced metal site, while the Tyr(10) residue of the native Aβ peptide donates the second electron. This Tyr(10) residue, the source of electron for the generation of partially reduced oxygen species (PROS, e.g., H(2)O(2)) is absent in rodents, which do not get affected by AD. When both heme and Cu are bound to the Aβ peptides, which is likely to happen physiologically, the amount of toxic PROS generated is maximum, implying that heme-Cu-Aβ complexes could potentially be most toxic for AD.
authors.affiliation: Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, India 700032.
authors.forename: Debajyoti
authors.initials: D
authors.lastname: Pramanik
authors.forename: Chandradeep
authors.initials: C
authors.lastname: Ghosh
authors.forename: Somdatta Ghosh
authors.initials: SG
authors.lastname: Dey
mesh_terms: D000042:Absorption; D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D003067:Coenzymes / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010544:Peroxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013057:Spectrum Analysis
chemical_list: D016229:Amyloid beta-Peptides; D003067:Coenzymes; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C433241:amyloid beta-protein (1-16); C078592:amyloid beta-protein (1-40); D006418:Heme; D003300:Copper; D010544:Peroxidases