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A plausible metal-free ancestral analogue of the Krebs cycle composed entirely of α-ketoacids

Nature Chemistry volume 12, pages 1016–1022 (2020)Cite this article

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Abstract

Efforts to decipher the prebiotic roots of metabolic pathways have focused on recapitulating modern biological transformations, with metals typically serving in place of cofactors and enzymes. Here we show that the reaction of glyoxylate with pyruvate under mild aqueous conditions produces a series of α-ketoacid analogues of the reductive citric acid cycle without the need for metals or enzyme catalysts. The transformations proceed in the same sequence as the reverse Krebs cycle, resembling a protometabolic pathway, with glyoxylate acting as both the carbon source and reducing agent. Furthermore, the α-ketoacid analogues provide a natural route for the synthesis of amino acids by transamination with glycine, paralleling the extant metabolic mechanisms and obviating the need for metal-catalysed abiotic reductive aminations. This emerging sequence of prebiotic reactions could have set the stage for the advent of increasingly sophisticated pathways operating under catalytic control.

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Fig. 1: The α-ketoacid pathway resembles transformations within the r-TCA and glyoxylate cycles.
Fig. 2: The α-ketoacid analogue pathway generated by the reaction of glyoxylate with pyruvate.
Fig. 3: The glyoxylate-dependent reduction of maloyl formate (III) to α-ketoglutarate (IV).
Fig. 4: Reaction progression of the α-ketoacid pathway with time.
Fig. 5: The transamination of α-ketoacids and glycine into α-amino acids and glyxoylate.

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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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Acknowledgements

This work was jointly supported by NSF and the NASA Astrobiology Program under the Center for Chemical Evolution (grant no. CHE-1504217) and by a NASA Exobiology grant to R.K. (80NSSC18K1300). G.S. acknowledges a Henry Dreyfus Teacher-Scholar Award.

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Authors and Affiliations

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

    R. Trent Stubbs & Greg Springsteen

  2. NSF-NASA Center for Chemical Evolution, Atlanta, GA, USA

    R. Trent Stubbs, Mahipal Yadav, Ramanarayanan Krishnamurthy & Greg Springsteen

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

    Mahipal Yadav & Ramanarayanan Krishnamurthy

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Contributions

R.T.S. and M.Y. contributed equally to this work. R.K., R.T.S and G.S. conceived the project. R.T.S, M.Y., R.K. and G.S. proposed and designed the experiments. R.T.S., G.S. and M.Y. carried out the experiments. All authors interpreted the data and discussed the experimental results. R.K. and G.S. supervised the research and wrote the paper with comments and feedback from R.T.S. and M.Y.

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Correspondence to Ramanarayanan Krishnamurthy or Greg Springsteen.

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Competing interests

R.K. and M.Y. declare they have no competing interests. G.S. and R.T.S. declare that a US non-provisional (16/746,124) and PCT application (PCT/US20/14023) have been filed covering the synthesis of organic acids and α-ketoacids. G.S. and R.T.S. own Aconabolics LLC, a company with commercial interests in using α-ketoacids as diagnostic agents.

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Stubbs, R.T., Yadav, M., Krishnamurthy, R. et al. A plausible metal-free ancestral analogue of the Krebs cycle composed entirely of α-ketoacids. Nat. Chem. 12, 1016–1022 (2020). https://doi.org/10.1038/s41557-020-00560-7

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