Abstract
Aspartic acid (Asp) residues in peptides and proteins are prone to nonenzymatic stereoinversion and/or isomerization to form three types of isomerized Asp residues (L-β-Asp, D-α-Asp, and D-β-Asp) via a five-membered ring succinimide intermediate. These isomerized Asp residues are detected more frequently in aged tissues. However, stereoinversion and/or isomerization of glutamic acid (Glu) residues having a chemical structure similar to Asp residues are hardly detected in proteins. In this study, we investigate computationally the formation mechanism of the cyclic imide, i.e., amino-glutarimidyl (Agl) from Glu residues, with water molecules as catalyst. We study the reaction mechanism by using quantum chemical B3LYP/6-31+G(d,p) density functional theory calculations. All calculations are performed by using model compounds in which a Glu residue is capped with acetyl and methylamino groups on the N- and C-termini, respectively. Agl formation consists of the three steps of iminolization, cyclization, and dehydration, and two water molecules acting as proton-relay mediators catalyze all three steps. The calculated activation energy for Agl formation from Glu residues is 30.3 kcal mol−1, which is somewhat greater than found experimentally for Asp-residue stereoinversion. This calculation suggests that in vivo Glu-residue stereoinversion is unlikely to occur because of the high activation barrier.
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