Proteins are composed of l‐amino acids, but nucleic acids and most oligosaccharides contain d‐sugars as building blocks. It is interesting to ask whether this is a coincidence or a consequence of the functional interplay of these biomolecules. One reaction that provides an opportunity to study this interplay is the formation of phosphoramidate‐linked peptido RNA from amino acids and ribonucleotides in aqueous condensation buffer. Here we report how the diastereoselectivity of the first peptide coupling of the peptido RNA pathway can be determined in situ by NMR spectroscopy. When a racemic mixture of an amino acid ester was allowed to react with an 5′‐aminoacidyl nucleotide, diastereomeric ratios of up to 72 : 28 of the resulting dipeptido nucleotides were found by integration of 31P‐ or 1H‐NMR peaks. The highest diastereomeric excess was found for the homochiral coupling product d‐Ser‐d‐Trp, phosphoramidate‐linked to adenosine 5′‐monophosphate with its d‐ribose ring. When control reactions with an N‐acetyl amino acid and valine methyl ester were run in organic solvent, the diastereoselectivity was found to be lower, with diastereomeric ratios≤62 : 38. The results from the exploratory study thus indicate that the ribonucleotide residue not only facilitates the coupling of lipophilic amino acids in aqueous medium but also the formation of a homochiral dipeptide. The methodology described here may be used to search for other stereoselective reactions that shed light on the origin of homochirality.
Protein adsorption is usually regarded as the main reason for filter fouling in sterile filtration of protein formulations. To achieve a better insight into this phenomenon, protein adsorption was studied during filtration of stabilized bovine serum albumin (BSA) and γ‐globulin formulations through 0.2‐µm microfilter membranes by inverse liquid chromatography (ILC). Adsorption processes can be studied with this method by measurement of breakthrough curves. The change of the concentration in the fluid phase is measured with high accuracy by an inline UV‐detector.
The formation of peptides from amino acids is one of the processes associated with life. Because of the dominant role of translation in extant biology, peptide‐forming processes that are RNA induced are of particular interest. We have previously reported the formation of phosphoramidate‐linked peptido RNAs as the products of spontaneous condensation reactions between ribonucleotides and free amino acids in aqueous solution. We now asked whether four‐helix bundle (4HB) DNA or RNA folding motifs with a single‐ or double‐nucleotide gap next to a 5’‐phosphate can act as reaction sites for phosphoramidate formation. For glycine, this was found to be the case, whereas phenylalanine and tryptophan showed accelerated formation of peptides without a covalent link to the nucleic acid. Free peptides with up to 11 tryptophan or phenylalanine residues were found in precipitates forming in the presence of gap‐containing DNA or RNA 4HBs. Control experiments using motifs with just a nick or primer alone did not have the same effect. Because folded structures with a gap in a double helix are likely products of hybridization of strands formed in statistically controlled oligomerization reactions, our results are interesting in the context of prebiotic scenarios. Independent of a putative role in evolution, our findings suggest that for some aromatic amino acids an RNA‐induced pathway for oligomerization exists that does not have a discernable link to translation.
The origin of homochirality is one of the unresolved issues of prebiotic chemistry. Why are the amino acids found in proteins of the l configuration? Perhaps peptido nucleotides could have played a role as transitional species, as suggested visually by the Archaeopteryx in the image. It was recently shown that these phosphoramidate‐linked species form spontaneously from simple precursors. Now, the diastereoselectivity of the the dipeptide‐forming step has been determined by in‐situ NMR spectroscopy, revealing that homochiral products are preferred. This is reported in the Full Paper by C. Richert et al. (DOI: 10.1002/chem.202101630).
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