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Computational Studies on Water-Catalyzed Mechanisms for Stereoinversion of Glutarimide Intermediates Formed from Glutamic Acid Residues in Aqueous Phase

1
Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi 468-8503, Japan
2
Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
3
Department of Pharmacy, Kinjo Gakuin University, 2–1723 Omori, Moriyama-ku, Nagoya, Aichi 463-8521, Japan
4
Institute for Protein Research, Osaka University, 3–2 Yamadaoka, Suita, Osaka 565-0871, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(10), 2410; https://doi.org/10.3390/ijms20102410
Received: 26 April 2019 / Revised: 10 May 2019 / Accepted: 14 May 2019 / Published: 15 May 2019
(This article belongs to the Special Issue DFT Applications to Biomolecules and Complex Reactions)
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Abstract

Aspartic acid (Asp) residues are prone to non-enzymatic stereoinversion, and Asp-residue stereoinversion is believed to be mediated via a succinimide (SI) intermediate. The stereoinverted Asp residues are believed to cause several age-related diseases. However, in peptides and proteins, few studies have reported the stereoinversion of glutamic acid (Glu) residues whose structures are similar to that of Asp. We previously presumed that Glu-residue stereoinversion proceeds via a glutarimide (GI) intermediate and showed that the calculated activation barriers of SI- and GI-intermediate stereoinversion are almost equivalent in the gas phase. In this study, we investigated the stereoinversion pathways of the l-GI intermediate in the aqueous phase using B3LYP density functional methods. The calculated activation barrier of l-GI-intermediate stereoinversion in the aqueous phase was approximately 36 kcal·mol−1, which was much higher than that in the gas phase. Additionally, as this activation barrier exceeded that of Asp-residue stereoinversion, it is presumed that Glu-residue stereoinversion has a lower probability of proceeding under physiological conditions than Asp-residue stereoinversion. View Full-Text
Keywords: d-amino acid residues; non-enzymatic reaction; stereoinversion; density functional theory d-amino acid residues; non-enzymatic reaction; stereoinversion; density functional theory
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Nakayoshi, T.; Fukuyoshi, S.; Kato, K.; Kurimoto, E.; Oda, A. Computational Studies on Water-Catalyzed Mechanisms for Stereoinversion of Glutarimide Intermediates Formed from Glutamic Acid Residues in Aqueous Phase. Int. J. Mol. Sci. 2019, 20, 2410.

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