Kinetics of serotonin oxidation by heme-Aβ relevant to Alzheimer's disease

Serotonin (5-HT) is an essential neurotransmitter for cognitive functions and formation of new memories. A deficit in 5-HT dependent neuronal activity is somewhat specific for Alzheimer's disease. Metal-mediated oxidative degradation of neurotransmitters by Aβ bound to metals has been investigated. Heme-bound Aβ is found to catalyze the oxidative degradation of 5-HT leading to the formation of neurotoxic products dihydroxybitryptamine and tyrptamine-4,5-dione. The catalytic degradation of 5-HT is of first order with respect to both heme-Aβ and H2O2, and the maximum rate of 5-HT oxidation is obtained at physiological pH (pH 7-7.5). pH perturbation of the binding affinity of heme-Aβ complex for 5-HT indicates that the binding of the substrate (5-HT) is not the rate-determining step. Arg5 acts as a second-sphere residue facilitating the O-O bond cleavage, the mutation of which leads to a decrease in the rate of 5-HT oxidation. The pull effect of the Arg5 residue tends to facilitate the generation of the active oxidant, Compound I, below neutral pH, while the ionization of the phenol group of the substrate facilitates the generation of the active substrate above neutral pH. A combination of these two opposing effects results in the highest activity at physiological pH. Apart from the Arg5 residue, the Tyr10 residue is found to play a vital role in the 5-HT oxidation by heme-Aβ complexes.