Evolutionary Importance of the Intramolecular Pathways of Hydrolysis of Phosphate Ester Mixed Anhydrides with Amino Acids and Peptides

Abstract

Aminoacyl adenylates (aa-AMPs) constitute essential intermediates of protein biosynthesis. Their polymerization in aqueous solution has often been claimed as a potential route to abiotic peptides in spite of a highly efficient CO2-promoted pathway of hydrolysis. Here we investigate the efficiency and relevance of this frequently overlooked pathway from model amino acid phosphate mixed anhydrides including aa-AMPs. Its predominance was demonstrated at CO2 concentrations matching that of physiological fluids or that of the present-day ocean, making a direct polymerization pathway unlikely. By contrast, the occurrence of the CO2-promoted pathway was observed to increase the efficiency of peptide bond formation owing to the high reactivity of the N-carboxyanhydride (NCA) intermediate. Even considering CO2 concentrations in early Earth liquid environments equivalent to present levels, mixed anhydrides would have polymerized predominantly through NCAs. The issue of a potential involvement of NCAs as biochemical metabolites could even be raised. The formation of peptide–phosphate mixed anhydrides from 5(4H)-oxazolones (transiently formed through prebiotically relevant peptide activation pathways) was also observed as well as the occurrence of the reverse cyclization process in the reactions of these mixed anhydrides. These processes constitute the core of a reaction network that could potentially have evolved towards the emergence of translation.

The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

“…Lastly, a high yield in DKP was obtained from the mixed anhydride with methyl phosphate, which is relevant to any kind of polymerisation of α-amino acids mixed anhydrides such as aminoacyl adenylates. It definitely disqualify this process as a possible pathway for prebiotic peptide formation in addition to the observation of a fast CO 2 -promoted conversion of aminoacyl adenylates into N-carboxyanhydrides (NCAs) preceding any possibility of polymerization (Liu et al 2014). The results presented in Table 1 show that the final yield in DKP is strongly dependent on the lifetime of the activated form of the dipeptide adduct.…”

Kinetic Barriers and the Self‐organization of Life

“…The corresponding process is predominant for CO 2 concentrations in equilibrium with the atmosphere (ca. 30–40 μM at pH 6.5) 52. The efficiency of CO 2 , as a catalyst composed of three atoms only, demonstrates that a significant part of enzyme rate accelerations can be brought about by very simple entities, without requiring the presence of a tightly structured binding site complementary to the transition state.…”

“…Induced intramolecularity was observed as a catalytic tool that could promote rate increases by several orders of magnitude using simple catalysts, and its contribution at early stages of evolution has been proposed 49. As an example meaningful for the evolution of the biochemical activation of α‐amino acids and for the evolution of translation, the efficiency of CO 2 as a catalyst for the conversion of aminoacyl adenylates through NCA ( N ‐carboxyanhydride) intermediates (Scheme ) was recently demonstrated 52. The corresponding process is predominant for CO 2 concentrations in equilibrium with the atmosphere (ca.…”

“…In the absence of enzymes, the conversion of ATP into aminoacyl adenylate is slow and thermodynamically unfavourable 71,72. Moreover, aminoacyl adenylates formed in this way would have a very short lifetime, owing to the CO 2 ‐promoted pathway (Scheme ), which questions the way through which they have been introduced into the metabolism of amino acids 52. The last issue, regarding the plausibility of an early role of phosphoanhydrides, is the need for an abiotic pathway to produce them at a scale sufficient for feeding the metabolism of early cellular living organisms.…”

A Chemical Engineering Perspective on the Origins of Life

“…Amide and phosphodiester bonds are typically formed through condensation reactions (i.e., generating water), which is thermodynamically unfavorable in an aqueous solution such as the ocean. Catalysts are needed to increase the forward rate of polymerization, and even then the monomers often require additional chemical modification, or "activation," to achieve significant length and yield [84]. For these reasons, alternative monomers and their polymers have also been proposed as pathways toward modern biopolymers.…”