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Catalysts 2017, 7(12), 363; doi:10.3390/catal7120363

Racemization of Serine Residues Catalyzed by Dihydrogen Phosphate Ion: A Computational Study

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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Received: 26 October 2017 / Revised: 16 November 2017 / Accepted: 22 November 2017 / Published: 27 November 2017
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Abstract

Spontaneous, nonenzymatic reactions in proteins are known to have relevance to aging and age-related diseases, such as cataract and Alzheimer’s disease. Among such reactions is the racemization of Ser residues, but its mechanism in vivo remains to be clarified. The most likely intermediate is an enol. Although being nonenzymatic, the enolization would need to be catalyzed to occur at a biologically relevant rate. In the present study, we computationally found plausible reaction pathways for the enolization of a Ser residue where a dihydrogen phosphate ion, H2PO4, acts as a catalyst. The H2PO4 ion mediates the proton transfer required for the enolization by acting simultaneously as both a general base and a general acid. Using the B3LYP density functional theory method, reaction pathways were located in the gas phase and hydration effects were evaluated by single-point calculations using the SM8 continuum model. The activation barriers calculated for the reaction pathways found were around 100 kJ mol−1, which is consistent with spontaneous reactions occurring at physiological temperature. Our results are also consistent with experimental observations that Ser residue racemization occurs more readily in flexible regions in proteins. View Full-Text
Keywords: serine residue; racemization; nonenzymatic reaction; phosphate catalysis; dihydrogen phosphate ion; enolization; proton transfer; computational chemistry; density functional theory serine residue; racemization; nonenzymatic reaction; phosphate catalysis; dihydrogen phosphate ion; enolization; proton transfer; computational chemistry; density functional theory
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Takahashi, O.; Kirikoshi, R.; Manabe, N. Racemization of Serine Residues Catalyzed by Dihydrogen Phosphate Ion: A Computational Study. Catalysts 2017, 7, 363.

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