title: Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion.
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-1after 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. ohgi@tohoku-mpu.ac.jp.
authors.forename: Ohgi
authors.initials: O
authors.lastname: Takahashi
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. kirikoshi@tohoku-mpu.ac.jp.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kirikoshi
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. manabe@tohoku-mpu.ac.jp.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Manabe
mesh_terms: D002384:Catalysis; D007477:Ions / Q000737:chemistry; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D013237:Stereoisomerism; D013388:Succinimides / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D007477:Ions; D010455:Peptides; D010710:Phosphates; D011506:Proteins; D013388:Succinimides; C032620:succinimide
keywords: aspartic acid residue; buffer catalysis; computational chemistry; density functional theory; dihydrogen phosphate ion; enolization; nonenzymatic reaction; proton transfer; racemization; succinimide