Chemoenzymatic Synthesis of Poly-l-lysine via Esterification with Alcohol in One-Pot

Chemoenzymatic polymerization (CEP) using enzymes as catalysts is gaining attention as an environmentally friendly method for synthesizing polypeptides. This method proceeds under mild conditions in aqueous solvents and leverages the substrate specificity of enzymes, allowing polymerization reactions to occur without the need to protect reactive side-chain functional groups. However, the monomers used must have esterified C-termini, such as amino acids or oligopeptides. In this study, we used l-lysine (Lys-OH) as a model example and performed one-pot CEP with papain without isolating the esterified lysine. Esterification of Lys-OH was achieved by using hydrochloric acid as a catalyst in ethanol, and one-pot polymerization resulted in poly-l-lysine (polyLys) with a peak top degree of polymerization (DP) of 6 and a maximum DP of 18, with a 31% conversion from the nonesterified lysine. The obtained polyLys was all α-linked, demonstrating that regioselective polymerization was successfully achieved even with one-pot CEP.