The Strecker reaction of aldehydes is the pre-eminent pathway to explain the prebiotic origins of α-amino acids. However, biology employs transamination of α-ketoacids to synthesize amino acids which are then transformed to nucleobases, implying an evolutionary switch—abiotically or biotically—of a prebiotic pathway involving the Strecker reaction into today’s biosynthetic pathways. Here we show that α-ketoacids react with cyanide and ammonia sources to form the corresponding α-amino acids through the Bucherer–Bergs pathway. An efficient prebiotic transformation of oxaloacetate to aspartate via N-carbamoyl aspartate enables the simultaneous formation of dihydroorotate, paralleling the biochemical synthesis of orotate as the precursor to pyrimidine nucleobases. Glyoxylate forms both glycine and orotate and reacts with malonate and urea to form aspartate and dihydroorotate. These results, along with the previously demonstrated protometabolic analogues of the Krebs cycle, suggest that there can be a natural emergence of congruent forerunners of biological pathways with the potential for seamless transition from prebiotic chemistry to modern metabolism.
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The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information.
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This work was jointly supported by NSF and the NASA Astrobiology Program under the NSF Center for Chemical Evolution, CHE-1504217, NASA Exobiology grant, 80NSSC18K1300 (to R.K.) and a grant from the Simons Foundation, 327124FY19 (to R.K.). We thank L. Leman and J. Peretó for feedback on the manuscript.
The authors declare no competing interests.
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The α-amino acids formed as products have the potential to compete and react with the starting α-ketoacids under the Bucherer-Bergs reaction conditions. Starting from pyruvate and cyanide, in the presence of glycine, only the adduct 4a formed (top pathway), and the substituted hydantoin 5f is not observed (Supplementary Figs. 56–57). When ammonia is present, the reaction is channelled towards the formation of 5-methylhydantoin 6 (bottom pathway, Supplementary Figs. 60–61). This is because while the aminonitrile adduct 4 is able to form the isocyanate intermediate 5c, the amino acid–nitrile adduct 4a cannot form the corresponding isocyanate intermediate leading to hydantoin 5f since the obligate intermediate 5e lacks the hydrogen atom necessary for the ring opening reaction (when compared to 5b)32.
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Pulletikurti, S., Yadav, M., Springsteen, G. et al. Prebiotic synthesis of α-amino acids and orotate from α-ketoacids potentiates transition to extant metabolic pathways. Nat. Chem. 14, 1142–1150 (2022). https://doi.org/10.1038/s41557-022-00999-w