Quantum Chemical Calculations of the Nonenzymatic Bicarbonate Ion-Catalyzed Lactamization of Ornithine Residues to Identify the Components of Primitive Proteins

Ornithine (Orn) is biochemically significant amino acid and has a structure similar to lysine, yet a noncanonical amino acid. When Orn is incorporated into a peptide chain, irreversible nonenzymatic C-terminal peptide cleavage and lactamization occur, inhibiting the synthesis of a peptide chain. The Orn reactivity is high, and likely to proceed even in the absence of enzymes. Nonenzymatic reactions could proceed with prebiotic catalysts that existed on the primitive Earth and may have played a crucial role in the origin of proteins. However, the mechanisms of these reactions have not been studied in great detail. In this study, quantum chemical calculations of these reactions were performed using the model compound Ac-Orn-NMe (Ac = acetyl, NMe = methylamino). Two reaction stages were considered: cyclization and C-terminal cleavage. Because the <i>gem</i>-hydroxylamine intermediate structure is diastereomeric, reaction pathways involving both R- and S-configured intermediates were investigated. The activation barriers for the Orn lactamization involving R- and S-intermediates with bicarbonate ions as a catalyst were estimated to be 82.4 and 76.6 kJ mol^-1, respectively. Thus, the Orn lactamization can proceed easily compared to lysine. The high reactivity of Orn may be the reason for the exclusion of Orn from the Magic 20.