10.1021/ja204628b.s001 Debajyoti Pramanik Debajyoti Pramanik Chandradeep Ghosh Chandradeep Ghosh Somdatta Ghosh Dey Somdatta Ghosh Dey Heme–Cu Bound Aβ Peptides: Spectroscopic Characterization, Reactivity, and Relevance to Alzheimer’s Disease American Chemical Society 2011 heme electron Tyr 10 residue β peptides PROS H 2O O 2 Cu exhibits peroxidase activity complex AD 2011-10-05 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Heme_Cu_Bound_A_Peptides_Spectroscopic_Characterization_Reactivity_and_Relevance_to_Alzheimer_s_Disease/2607394 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<sup>+</sup>–Aβ and heme (Fe<sup>2+</sup>)–Aβ complexes reduce O<sub>2</sub> to H<sub>2</sub>O<sub>2</sub> quantitatively. Only one of the two electrons that are required for the reduction of O<sub>2</sub> to H<sub>2</sub>O<sub>2</sub> is derived from the reduced metal site, while the Tyr<sup>10</sup> residue of the native Aβ peptide donates the second electron. This Tyr<sup>10</sup> residue, the source of electron for the generation of partially reduced oxygen species (PROS, e.g., H<sub>2</sub>O<sub>2</sub>) 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.