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Prebiotic synthesis of α-amino acids and orotate from α-ketoacids potentiates transition to extant metabolic pathways

Nature Chemistry volume 14, pages 1142–1150 (2022)Cite this article

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Abstract

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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Fig. 1: Comparison of the prebiotic and biotic routes to α-amino acids.
Fig. 2: Mechanistic pathway for the conversion of α-ketoacids to α-amino acids via the Bucherer–Bergs reaction.
Fig. 3: Synthesis of α-amino acids and orotate from α-ketoacids using DAP and cyanide.
Fig. 4: Reaction of α-ketoacid condensation products with ammonia sources produces compounds found in the Krebs cycle and its secondary metabolites.
Fig. 5: The emergence of the various pathways with incremental systems-chemistry complexity.

Data availability

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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Acknowledgements

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.

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Author notes

  1. These authors contributed equally: Sunil Pulletikurti, Mahipal Yadav.

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    Sunil Pulletikurti, Mahipal Yadav & Ramanarayanan Krishnamurthy

  2. NSF-NASA Center for Chemical Evolution, Georgia Institute of Technology, Atlanta, GA, USA

    Sunil Pulletikurti, Greg Springsteen & Ramanarayanan Krishnamurthy

  3. Department of Chemistry, Furman University, Greenville, SC, USA

    Greg Springsteen

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  1. Sunil Pulletikurti
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Contributions

R.K. proposed the project. G.S. and R.K. designed and supervised research. S.P and M.Y. designed and performed the experiments and collected the data. S.P., M.Y., G.S. and R.K. analysed data. R.K. wrote the manuscript with feedback and edits from S.P., M.Y. and G.S.

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Correspondence to Ramanarayanan Krishnamurthy.

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Extended data

Extended Data Fig. 1 Non-interference from α-amino acids in the Bucherer–Bergs reaction.

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.

Supplementary information

Supplementary Information

General experimental, experimental procedures, Supplementary Figs. 1–90, Tables 1–3, Schemes 1 and 2, references and NMR spectra.

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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

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