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Synthesis and breakdown of universal metabolic precursors promoted by iron


Life builds its molecules from carbon dioxide (CO2) and breaks them back down again through the intermediacy of just five metabolites, which are the universal hubs of biochemistry1. However, it is unclear how core biological metabolism began and why it uses the intermediates, reactions and pathways that it does. Here we describe a purely chemical reaction network promoted by ferrous iron, in which aqueous pyruvate and glyoxylate—two products of abiotic CO2 reduction2,3,4—build up 9 of the 11 intermediates of the biological Krebs (or tricarboxylic acid) cycle, including all 5 universal metabolic precursors. The intermediates simultaneously break down to CO2 in a life-like regime that resembles biological anabolism and catabolism5. Adding hydroxylamine6,7,8 and metallic iron into the system produces four biological amino acids in a manner that parallels biosynthesis. The observed network overlaps substantially with the Krebs and glyoxylate cycles9,10, and may represent a prebiotic precursor to these core metabolic pathways.

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All data are available in the main text, Extended Data Figs. 1, 2 and the Supplementary Information (Supplementary Materials and Methods, Supplementary Figs. 129 and Supplementary Tables 14).

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We thank W. F. Martin and D. Segrè for discussions. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 639170) and from the French Agence Nationale de la Recherche (ANR) Laboratoires d’Excellence ‘Chemistry of Complex Systems’ (ANR-10-LABX-0026 CSC).

Reviewer information

Nature thanks Eric Smith, Peter Strazewski and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

J.M. supervised the research and the other authors performed the experiments. All authors contributed intellectually throughout the study. J.M. and K.B.M wrote the paper, and K.B.M. and S.J.V. assembled the Supplementary Information.

Competing interests

The authors declare no competing interests.

Correspondence to Joseph Moran.

Extended data figures and tables

  1. Extended Data Fig. 1 Screen for transition metal promoters.

    These GC chromatograms show the reaction networks that arise from pyruvate and glyoxylate at 70 °C, as promoted by different transition metal ions (qualitative screen).

  2. Extended Data Fig. 2 Calibration lines for carboxylic acids.

    Shown are the correlations between the concentrations of aqueous solutions of carboxylic acids (glyoxylic, glycolic, oxalic, malonic, levulinic, mesaconic, and hydroxyketoglutaric plus oxopentenedioic acids) and the measured GC peak area. Error bars correspond to the standard deviation (three independent runs). Orange lines show the 95% confidence bounds computed for second-degree polynomial fits (OriginPro). Calibration lines for glycine, aspartic acid and glutamic acid are shown in Supplementary Fig. 10. Calibration lines for the remaining compounds detected here (pyruvate, malate, fumarate, succinate, α-ketoglutarate, isocitrate, cis-aconitate, tricarballylate and alanine) are identical to those we reported previously for the same analytical set-up9 (Supplementary Table 1).

Supplementary information

  1. Supplementary Information

    This file contains Supplementary Materials and Methods, Supplementary References, Supplementary Figures 1-29 and Supplementary Tables 1-4.

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Fig. 1: Fe2+-promoted synthesis and breakdown of the precursors of biological metabolism.
Fig. 2: Comparison of the observed reaction network with the TCA and glyoxylate cycles.
Extended Data Fig. 1: Screen for transition metal promoters.
Extended Data Fig. 2: Calibration lines for carboxylic acids.


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