A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron.
The β-amyloid precursor protein (APP), which is a key player in Alzheimer's disease, was recently reported to possess an Fe(II) binding site within its E2 domain which exhibits ferroxidase activity [Duce et al. 2010, Cell 142: 857]. The putative ligands of this site were compared to those in the ferroxidase site of ferritin. The activity was indirectly measured using transferrin, which scavenges the Fe(III) product of the reaction. A 22-residue synthetic peptide, named FD1, with the putative ferroxidase site of APP, and the E2 domain of APP were each reported to exhibit 40% of the ferroxidase activity of APP and of ceruloplasmin. It was also claimed that the ferroxidase activity of APP is inhibited by Zn(II) just as in ferritin. We measured the ferroxidase activity indirectly (i) by the incorporation of the Fe(III) product of the ferroxidase reaction into transferrin and directly (ii) by monitoring consumption of the substrate molecular oxygen. The results with the FD1 peptide were compared to the established ferroxidase activities of human H-chain ferritin and of ceruloplasmin. For FD1 we observed no activity above the background of non-enzymatic Fe(II) oxidation by molecular oxygen. Zn(II) binds to transferrin and diminishes its Fe(III) incorporation capacity and rate but it does not specifically bind to a putative ferroxidase site of FD1. Based on these results, and on comparison of the putative ligands of the ferroxidase site of APP with those of ferritin, we conclude that the previously reported results for ferroxidase activity of FD1 and - by implication - of APP should be re-evaluated.
Department of Biotechnology, Delft University of Technology, Delft, The Netherlands.
Kourosh Honarmand
KH
Ebrahimi
Peter-Leon
PL
Hagedoorn
Wilfred R
WR
Hagen
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001665:Binding Sites; D055162:Biocatalysis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D013816:Thermodynamics; D015032:Zinc / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D007501:Iron; D015032:Zinc; D010100:Oxygen