Abstract:
Ribosomal peptide synthesis (RPS) is orchestrated through the aminoacylation of RNAs by
aminoacyl-tRNA synthetase enzymes that are produced by RPS. This causal paradox, which
was established prior to the evolution of life’s last universal common ancestor, obscures the
origins of protein biosynthesis. To break this paradox, we set out to build a deterministic
model of the minimum reactivity required to initiate peptide biosynthesis.
The chemical unity and antiquity of life’s central metabolites provide compelling evidence
that a simple set of chemical reactions predicated the appearance of life on Earth, 1-2 and we
reasoned that rediscovering such a reaction network, and the rules that control it, would be the
key to uncovering the origins of peptide biosynthesis.
In this talk recent advances that suggest life’s nucleotides, 1,3 peptides, 3-7 and cofactors 8 are
predisposed structures will be presented. These results indicate that (biological) thioester
activation can direct RNA to intercept peptide synthesis, 9 which is an essential step towards
establishing life’s central dogma.
Selected references
[1] Powner + Nature 2009, 459, 239–242.
[2] Coggins + Nat. Chem. 2017, 9, 310–317.
[3] Islam + Nat. Chem. 2017, 9, 584–589.
[4] Canavelli + Nature 2019, 571, 546–549.
[5] Foden + Science 2020, 370, 865–869.
[6] Singh + J. Am. Chem. Soc. 2022, 144, 10151–10155
[7] Thoma + J. Am. Chem. Soc. 2023, 145, 3121–3130.
[8] Fairchild + Science 2024, 383, 911–918.
[9] Singh + Nature 2025, 644, 933–944