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Int. J. Mol. Sci. 2016, 17(10), 1698; doi:10.3390/ijms17101698

Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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Academic Editor: Mihai V. Putz
Received: 28 August 2016 / Revised: 22 September 2016 / Accepted: 30 September 2016 / Published: 10 October 2016
(This article belongs to the Special Issue Chemical Bond and Bonding 2016)
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Abstract

In proteins and peptides, d-aspartic acid (d-Asp) and d-β-Asp residues can be spontaneously formed via racemization of the succinimide intermediate formed from l-Asp and l-asparagine (l-Asn) residues. These biologically uncommon amino acid residues are known to have relevance to aging and pathologies. Although nonenzymatic, the succinimide racemization will not occur without a catalyst at room or biological temperature. In the present study, we computationally investigated the mechanism of succinimide racemization catalyzed by dihydrogen phosphate ion, H2PO4, by B3LYP/6-31+G(d,p) density functional theory calculations, using a model compound in which an aminosuccinyl (Asu) residue is capped with acetyl (Ace) and NCH3 (Nme) groups on the N- and C-termini, respectively (Ace–Asu–Nme). It was shown that an H2PO4 ion can catalyze the enolization of the Hα–Cα–C=O portion of the Asu residue by acting as a proton-transfer mediator. The resulting complex between the enol form and H2PO4 corresponds to a very flat intermediate region on the potential energy surface lying between the initial reactant complex and its mirror-image geometry. The calculated activation barrier (18.8 kcal·mol−1 after corrections for the zero-point energy and the Gibbs energy of hydration) for the enolization was consistent with the experimental activation energies of Asp racemization. View Full-Text
Keywords: succinimide; racemization; aspartic acid residue; nonenzymatic reaction; buffer catalysis; dihydrogen phosphate ion; enolization; proton transfer; computational chemistry; density functional theory succinimide; racemization; aspartic acid residue; nonenzymatic reaction; buffer catalysis; dihydrogen phosphate ion; enolization; proton transfer; computational chemistry; density functional theory
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Takahashi, O.; Kirikoshi, R.; Manabe, N. Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion. Int. J. Mol. Sci. 2016, 17, 1698.

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