Shared Pathways to Peptides in Biochemistry and Prebiotic Chemistry through Ester Amide Exchange Chemistry

The origin of life requires plausible pathways for the emergence of polymers under realistic early-Earth conditions. Increasing geological and geochemical evidence supports highly dynamic environments characterized by strong temperature gradients and fluctuating hydration states that repeatedly drive chemistry out of equilibrium. Wet–dry cycling in shallow settings can promote polymer formation by favoring condensation during dehydration and hydrolysis during rehydration, thereby imposing a rudimentary, persistence-based selection pressure. Here we highlight a conceptual chemical bridge between prebiotic polymer chemistry and extant biochemistry: ester-mediated amide formation via ester-amide exchange. In modern translation, peptide bond formation proceeds not by direct condensation of amino acids but by nucleophilic attack of the α-amine of the A-site aminoacyl-tRNA on the ester linkage of the P-site peptidyl-tRNA at the ribosomal peptidyl transferase center. Strikingly similar chemistry arises abiotically under wet–dry cycling in mixtures of hydroxy acids and amino acids, where dehydration readily generates esters that subsequently undergo ester-amide exchange to form depsipeptides, which are oligomers composed of mixed ester and amide linkages, without sophisticated catalysts. We argue that wet-dry cycling and ester-mediated exchange may outline a plausible continuum from non-coded depsipeptide formation to the refined ribosomal peptide synthesis, offering an experimentally tractable framework for interrogating the constraints that shaped early polymer evolution.