Prebiotic Catalytic Peptide Ligation Yields Proteinogenic Peptides by Intramolecular Amide Catalyzed Hydrolysis Facilitating Regioselective Lysine Ligation in Neutral Water
Year: 2022
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide The prebiotic origin of catalyst-controlled peptide synthesis is fundamental to understanding the emergence of life. Building on our recent discovery that thiols catalyze the ligation of amino acids, amides, and peptides with amidonitriles in neutral water, we demonstrate the outcome of ligation depends on pH and that high p K a primary thiols are the ideal catalysts. While the most rapid thiol catalyzed peptide ligation occurs at pH 8.5–9, the most selective peptide ligation, that tolerates all proteinogenic side chains, occurs at pH 7. We have also identified the highly selective mechanism by which the intermediate peptidyl amidines undergo hydrolysis to α-peptides while demonstrating that the hydrolysis of amidines with nonproteinogenic structures, such as β- and γ-peptides, displays poor selectivity. Notably, this discovery enables the highly α-selective protecting-group-free ligation of lysine peptides at neutral pH while leaving the functional ε-amine side chain intact.
DOI: 10.1021/jacs.2c03486
Institutions: University College London, King's College London
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Awards: G1209682180, DTP - University College London, G316605910, G3937387470, An Investigation of Multicomponent Azole Chemistry within a Generational System for the Expression the Canonical Genetic Structures, G5206295252, A 700 MHz broadband cryoprobe and NMR spectrometer at UCL Chemistry, G8248977208, G8545663432
OpenAlex ID: W4281777549