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Kinetics of serotonin oxidation by heme–Aβ relevant to Alzheimer’s disease

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Abstract

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.

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Acknowledgments

We thank SERC Fast Track Scheme SR/FT/CS-34/2010, Department of Science and Technology, Government of India and IACS for funding this research. S. M. is thankful to the Council of Scientific and Industrial Research, India, for a Junior Research Fellowship. M. S. is thankful to IACS-integrated Ph.D. programme for Junior Research Fellowship. We thank Professor T. K. Mandal of Polymer Science Unit, IACS, for allowing us to use his HPLC machine (Waters 1525 Separation Module) and Dr. Abhishek Dey for his helpful discussions.

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Authors and Affiliations

  1. Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, 700032, India

    Soumya Mukherjee, Manas Seal & Somdatta Ghosh Dey

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  1. Soumya Mukherjee
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  2. Manas Seal
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  3. Somdatta Ghosh Dey
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Correspondence to Somdatta Ghosh Dey.

Electronic supplementary material

Below is the link to the electronic supplementary material.

775_2014_1193_MOESM1_ESM.pdf

Area under the curve for 5-HT and residual 5-HT after oxidation obtained from HPLC data, separation of the 5-HT and its products by RP-HPLC after its incubation with excess heme–Aβ, Eadie-Hofstee plots of 5-HT oxidation by heme–Aβ(1–16), saturation plot of the initial rate of oxidation of 5-HT (ΔA 317nm/s) by heme- heme–Aβ(1–16) against various 5-HT concentration at different pH, absorption spectra of 5-HT titration to heme–Aβ(1–16) and K d values at different pH, absorption spectra of 5-HT titration heme-bound Tyr10Phe mutant of Aβ(1–16) at different pH values, 5HT titration with free heme are available online as ESI. (PDF 3121 kb)

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Mukherjee, S., Seal, M. & Dey, S.G. Kinetics of serotonin oxidation by heme–Aβ relevant to Alzheimer’s disease. J Biol Inorg Chem 19, 1355–1365 (2014). https://doi.org/10.1007/s00775-014-1193-7

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  • DOI: https://doi.org/10.1007/s00775-014-1193-7

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