Quantum chemical calculation of the nonenzymatic lactamization of ornithine and lysine residues catalysed by a single water molecule

Existing proteins are composed of approximately 20 types of amino acids known as Magic 20, but the reason underlying this limited number remains unclear. Ornithine (Orn) is similar to that of Lys, but Orn is not a constituent of proteins. When Orn is incorporated into a peptide chain, irreversible nonenzymatic lactamization and C-terminal side peptide cleavage occur, inhibiting peptide chain synthesis. However, the details of the reaction mechanisms have not been sufficiently elucidated. In this study, quantum chemical calculations were performed to explore the reaction pathway of the nonenzymatic lactamization of Orn and Lys residues, and the activation barriers were evaluated. The lactamization was assumed to proceed via a gem-hydroxylamine intermediate. Since the gem-hydroxylamine intermediate has diastereomers, both reaction pathways via the R- and S-configured intermediates were examined. In this study, a single water molecule was used as the catalyst. The activation barriers for the Orn lactamization via the R- and S-configured intermediates were 102 and 120 kJ mol−1, respectively. These values are comparable to the typical activation barriers for the nonenzymatic reactions of amino acid residues. By contrast, the activation barriers for the Lys lactamization were 158 and 145 kJ mol−1, suggesting that Lys lactamization is unlikely to proceed.