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Int. J. Mol. Sci. 2015, 16(1), 1613-1626; doi:10.3390/ijms16011613

Acetic Acid Can Catalyze Succinimide Formation from Aspartic Acid Residues by a Concerted Bond Reorganization Mechanism: A Computational Study

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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Academic Editor: Habil. Mihai V. Putz
Received: 13 December 2014 / Accepted: 4 January 2015 / Published: 12 January 2015
(This article belongs to the Special Issue Chemical Bond and Bonding 2015)
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Abstract

Succinimide formation from aspartic acid (Asp) residues is a concern in the formulation of protein drugs. Based on density functional theory calculations using Ace-Asp-Nme (Ace = acetyl, Nme = NHMe) as a model compound, we propose the possibility that acetic acid (AA), which is often used in protein drug formulation for mildly acidic buffer solutions, catalyzes the succinimide formation from Asp residues by acting as a proton-transfer mediator. The proposed mechanism comprises two steps: cyclization (intramolecular addition) to form a gem-diol tetrahedral intermediate and dehydration of the intermediate. Both steps are catalyzed by an AA molecule, and the first step was predicted to be rate-determining. The cyclization results from a bond formation between the amide nitrogen on the C-terminal side and the side-chain carboxyl carbon, which is part of an extensive bond reorganization (formation and breaking of single bonds and the interchange of single and double bonds) occurring concertedly in a cyclic structure formed by the amide NH bond, the AA molecule and the side-chain C=O group and involving a double proton transfer. The second step also involves an AA-mediated bond reorganization. Carboxylic acids other than AA are also expected to catalyze the succinimide formation by a similar mechanism. View Full-Text
Keywords: aspartic acid residue; nonenzymatic reaction; succinimide; density functional theory; computational chemistry; acetic acid; buffer catalysis; double proton transfer; concerted bond reorganization; protein drugs aspartic acid residue; nonenzymatic reaction; succinimide; density functional theory; computational chemistry; acetic acid; buffer catalysis; double proton transfer; concerted bond reorganization; protein drugs
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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. Acetic Acid Can Catalyze Succinimide Formation from Aspartic Acid Residues by a Concerted Bond Reorganization Mechanism: A Computational Study. Int. J. Mol. Sci. 2015, 16, 1613-1626.

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