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Molecules 2014, 19(8), 11440-11452; doi:10.3390/molecules190811440

Roles of Intramolecular and Intermolecular Hydrogen Bonding in a Three-Water-Assisted Mechanism of Succinimide Formation from Aspartic Acid Residues

Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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Received: 23 June 2014 / Revised: 20 July 2014 / Accepted: 23 July 2014 / Published: 4 August 2014
(This article belongs to the Special Issue Intramolecular Hydrogen Bonding)
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Abstract

Aspartic acid (Asp) residues in peptides and proteins are prone to isomerization to the β-form and racemization via a five-membered succinimide intermediate. These nonenzymatic reactions have relevance to aging and age-related diseases. In this paper, we report a three water molecule-assisted, six-step mechanism for the formation of succinimide from Asp residues found by density functional theory calculations. The first two steps constitute a stepwise iminolization of the C-terminal amide group. This iminolization involves a quintuple proton transfer along intramolecular and intermolecular hydrogen bonds formed by the C-terminal amide group, the side-chain carboxyl group, and the three water molecules. After a conformational change (which breaks the intramolecular hydrogen bond involving the iminol nitrogen) and a reorganization of water molecules, the iminol nitrogen nucleophilically attacks the carboxyl carbon of the Asp side chain to form a five-membered ring. This cyclization is accompanied by a triple proton transfer involving two water molecules, so that a gem-diol tetrahedral intermediate is formed. The last step is dehydration of the gem-diol group catalyzed by one water molecule, and this is the rate-determining step. The calculated overall activation barrier (26.7 kcal mol−1) agrees well with an experimental activation energy. View Full-Text
Keywords: aspartic acid residue; nonenzymatic reaction; succinimide intermediate; density functional theory; water catalysis; multiple proton transfer; amide-iminol tautomerism aspartic acid residue; nonenzymatic reaction; succinimide intermediate; density functional theory; water catalysis; multiple proton transfer; amide-iminol tautomerism
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Takahashi, O.; Kirikoshi, R.; Manabe, N. Roles of Intramolecular and Intermolecular Hydrogen Bonding in a Three-Water-Assisted Mechanism of Succinimide Formation from Aspartic Acid Residues. Molecules 2014, 19, 11440-11452.

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