Computational studies on non-succinimide-mediated stereoinversion mechanism of aspartic acid residues assisted by phosphate |
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Authors: | Tomoki Nakayoshi Shuichi Fukuyoshi Ohgi Takahashi |
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Institution: | 1. Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan;2. Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan |
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Abstract: | ABSTRACTAlthough nearly all of the amino acids that constitute proteins are l-amino acids, d-amino acid residues in human proteins have been recently reported. d-amino acid residues cause a change in the three-dimensional structure of proteins, and d-aspartic acid (Asp) residues are considered to be one of the causes of age-related diseases. The stereoinversion of Asp residues in peptides and proteins is thought to proceed via a succinimide intermediate; however, it has been reported that stereoinversion can occur even under conditions where a succinimide intermediate cannot be formed. In order to elucidate the non-succinimide-mediated stereoinversion pathway, we investigated the stereoinversion of l-Asp to d-Asp catalysed by phosphate and estimated the activation barrier using B3LYP/6?31+G(d,p) density functional theory (DFT) calculations. For the DFT calculations, a model compound in which the Asp residue is capped with acetyl and methyl-amino groups on the N- and C-termini, respectively, was used. The calculated activation barrier was not excessively high for the stereoinversion to occur in vivo. Therefore, this stereoinversion mechanism may compete with the succinimide-mediated mechanism. |
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Keywords: | Aspartic acid residue stereoinversion non-enzymatic reaction phosphate-catalysed density functional theory |
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