Redox Reactions of Copper Complexes Formed with Different -Amyloid Peptides and Their Neuropathalogical Relevance
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- 作者：Dianlu Jiang ; Lijie Men ; Jianxiu Wang ; Yi Zhang ; Sara Chickenyen ; Yinsheng Wang ; Feimeng Zhou
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：August 14, 2007
- 年：2007
- 卷：46
- 期：32
- 页码：9270 - 9282
- 全文大小：188K
- 年卷期：v.46,no.32(August 14, 2007)
- ISSN：1520-4995
文摘
The binding stoichiometry between Cu(II) and the full-length 
-amyloid A(1-42) and theoxidation state of copper in the resultant complex were determined by electrospray ionization-Fouriertransform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) and cyclic voltammetry. The sameapproach was extended to the copper complexes of A(1-16) and A(1-28). A stoichiometric ratio of1:1 was directly observed, and the oxidation state of copper was deduced to be 2+ for all of the complexes,and residues tyrosine-10 and methionine-35 are not oxidized in the A(1-42)-Cu(II) complex. Thestoichiometric ratio remains the same in the presence of more than a 10-fold excess of Cu(II). Redoxpotentials of the sole tyrosine residue and the Cu(II) center were determined to be ca. 0.75 and 0.08 V vsAg/AgCl [or 0.95 and 0.28 V vs normal hydrogen electrode (NHE)], respectively. More importantly, forthe first time, the A-Cu(I) complex has been generated electrochemically and was found to catalyzethe reduction of oxygen to produce hydrogen peroxide. The voltammetric behaviors of the three Asegments suggest that diffusion of oxygen to the metal center can be affected by the length andhydrophobicity of the A peptide. The determination and assignment of the redox potentials clarify somemisconceptions in the redox reactions involving A and provide new insight into the possible roles ofredox metal ions in the Alzheimer's disease (AD) pathogenesis. In cellular environments, the reductionpotential of the A-Cu(II) complex is sufficiently high to react with antioxidants (e.g., ascorbic acid)and cellular redox buffers (e.g., glutathione), and the A-Cu(I) complex produced could subsequentlyreduce oxygen to form hydrogen peroxide via a catalytic cycle. Using voltammetry, the A-Cu(II) complexformed in solution was found to be readily reduced by ascorbic acid. Hydrogen peroxide produced, inaddition to its role in damaging DNA, protein, and lipid molecules, can also be involved in the furtherconsumption of antioxidants, causing their depletion in neurons and eventually damaging the neuronaldefense system. Another possibility is that A-Cu(II) could react with species involved in the cascadeof electron transfer events of mitochondria and might potentially sidetrack the electron transfer processesin the respiratory chain, leading to mitochondrial dysfunction.
-amyloid A(1-42) and theoxidation state of copper in the resultant complex were determined by electrospray ionization-Fouriertransform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) and cyclic voltammetry. The sameapproach was extended to the copper complexes of A(1-16) and A(1-28). A stoichiometric ratio of1:1 was directly observed, and the oxidation state of copper was deduced to be 2+ for all of the complexes,and residues tyrosine-10 and methionine-35 are not oxidized in the A(1-42)-Cu(II) complex. Thestoichiometric ratio remains the same in the presence of more than a 10-fold excess of Cu(II). Redoxpotentials of the sole tyrosine residue and the Cu(II) center were determined to be ca. 0.75 and 0.08 V vsAg/AgCl [or 0.95 and 0.28 V vs normal hydrogen electrode (NHE)], respectively. More importantly, forthe first time, the A-Cu(I) complex has been generated electrochemically and was found to catalyzethe reduction of oxygen to produce hydrogen peroxide. The voltammetric behaviors of the three Asegments suggest that diffusion of oxygen to the metal center can be affected by the length andhydrophobicity of the A peptide. The determination and assignment of the redox potentials clarify somemisconceptions in the redox reactions involving A and provide new insight into the possible roles ofredox metal ions in the Alzheimer's disease (AD) pathogenesis. In cellular environments, the reductionpotential of the A-Cu(II) complex is sufficiently high to react with antioxidants (e.g., ascorbic acid)and cellular redox buffers (e.g., glutathione), and the A-Cu(I) complex produced could subsequentlyreduce oxygen to form hydrogen peroxide via a catalytic cycle. Using voltammetry, the A-Cu(II) complexformed in solution was found to be readily reduced by ascorbic acid. Hydrogen peroxide produced, inaddition to its role in damaging DNA, protein, and lipid molecules, can also be involved in the furtherconsumption of antioxidants, causing their depletion in neurons and eventually damaging the neuronaldefense system. Another possibility is that A-Cu(II) could react with species involved in the cascadeof electron transfer events of mitochondria and might potentially sidetrack the electron transfer processesin the respiratory chain, leading to mitochondrial dysfunction.