Thioesters provide a plausible prebiotic path to proto-peptides

Abstract

It is widely assumed that the condensation of building blocks into oligomers and polymers was important in the origins of life. High activation energies, unfavorable thermodynamics and side reactions are bottlenecks for abiotic peptide formation. All abiotic reactions reported thus far for peptide bond formation via thioester intermediates have relied on high energy molecules, which usually suffer from short half-life in aqueous conditions and therefore require constant replenishment. Here we report plausible prebiotic reactions of mercaptoacids with amino acids that result in the formation of thiodepsipeptides, which contain both peptide and thioester bonds. Thiodepsipeptide formation was achieved under a wide range of pH and temperature by simply drying and heating mercaptoacids with amino acids. Our results offer a robust one-pot prebiotically-plausible pathway for proto-peptide formation. These results support the hypothesis that thiodepsipeptides and thiol-terminated peptides formed readily on prebiotic Earth and were possible contributors to early chemical evolution.

Alternating co-synthesis of glycol nucleic acid (GNA) monomers with dicarboxylic acids via drying

“…When MA was used, which also has an a-hydroxyl group, a similar product distribution as the unsubstituted SA was observed, containing up to nine DHPT units (Fig. S5 and Table S3 24 and ester bonds with the a-NH 2 , -SH and -OH groups of the linker monomers, respectively. In the reaction of TMA with DHPT, additional mass peaks consistent with oligomers but with the loss of H 2 were also detected, suggesting disulfide bond formation.…”

“…S6–S8 and Tables S4–S6, ESI†), mass spectral peaks consistent with linear and branched oligomers containing DHPT and the respective DCAs were also observed. The presence of m / z signals consistent with Asp 3 DHPT, TMA 6 DHPT 4 and TA 6 DHPT 3 suggests the generation of peptide, thioester 24 and ester bonds with the α-NH 2 , –SH and –OH groups of the linker monomers, respectively. In the reaction of TMA with DHPT, additional mass peaks consistent with oligomers but with the loss of H 2 were also detected, suggesting disulfide bond formation.…”

Formation, stabilization and fate of acetaldehyde and higher aldehydes in an autonomously changing prebiotic system emerging from acetylene

“…The presence of sulfonic acids was also detected in the Murchison meteorite, even though a direct relevance for the origin-of-life remained uncommented 42 . Recent reports show the increased importance of sulfur functional groups, especially thiols, as precursors of protopeptides 43 and organocatalysts 44 .…”

Förster Resonance Energy Transfer Assay for Investigating the Reactivity of Thioesters in Biochemistry and Native Chemical Ligation

“…Examples of such transformations are protein splicing, 12,13 sortase-mediated crosslinking, 14,15 the ubiquitylation of proteins by E2/E3 ligases, 16,17 and the synthesis of peptides by nonribosomal peptide synthetase (NRPS) enzyme cluster assembly lines 18−20 (Figure 1). Furthermore, thioesters have been proposed to play central roles in the chemistry preceding the origins of life; for example, as intermediates in amino acid synthesis, 21 "protopeptide" synthesis, 22 and as energy-rich molecules in prebiotic chemistry. 4,23 The reactivity of thioesters and reversible nature of the thiol−thioester exchange reaction in an aqueous medium have been exploited in numerous applications ranging from dynamic combinatorial chemistry, 24−26 template-directed self-assembly of peptide nucleic acids, 27 oscillatory networks, 28 and chemical protein synthesis by the "native chemical ligation" (NCL) reaction, 29−31 which takes further advantage of an intramolecular S → N acyl shift at N-terminal cysteine residues.…”

“…Examples of such transformations are protein splicing, , sortase-mediated crosslinking, , the ubiquitylation of proteins by E2/E3 ligases, , and the synthesis of peptides by nonribosomal peptide synthetase (NRPS) enzyme cluster assembly lines − (Figure ). Furthermore, thioesters have been proposed to play central roles in the chemistry preceding the origins of life; for example, as intermediates in amino acid synthesis, “protopeptide” synthesis, and as energy-rich molecules in prebiotic chemistry. , …”