Synthesis and breakdown of universal metabolic precursors promoted by iron
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Abstract
Life builds its molecules from carbon dioxide (CO 2) and breaks them back down again through the intermediacy of just five metabolites, which are the universal hubs of biochemistry 1. 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 CO 2 reduction 2-4-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 CO 2 in a life-like regime that resembles biological anabolism and catabolism 5. Adding hydroxylamine 6-8 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 cycles 9,10, and may represent a prebiotic precursor to these core metabolic pathways.
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Moran and coworkers have reported that pyruvate and glyoxylate react in warm iron-rich water to produce most of the intermediates and biological pathways of the TCA cycle, in addition to some amino acids.
“In this regard, Moran and coworkers have reported that pyruvate and glyoxylate react in warm iron-rich water to produce most of the intermediates and biological pathways of the TCA cycle, in addition to some amino acids.21”
From The protometabolic nature of prebiotic chemistry (2023) · cites this paper as [21]
The Abstract reports that pyruvate and glyoxylate form a network in warm iron-rich water that includes nine of eleven TCA-cycle intermediates and seven of its eleven reactions. It also reports four amino acids, but only after hydroxylamine and Fe0 are added; the claim omits that condition. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSamples generated under such conditions were analysed by GC-MS and NMR, revealing a significant production of acetate, pyruvate, malate, fumarate, succinate, α-ketoglutarate, isocitrate and aconitate.
“Samples generated under such conditions were analysed by GC-MS and NMR, revealing a significant production of acetate, pyruvate, malate, fumarate, succinate, α-ketoglutarate, isocitrate and aconitate (Scheme 9).”
From The protometabolic nature of prebiotic chemistry (2023) · cites this paper as [21]
The paper’s opening section reports that all eight listed compounds were detected by GC-MS within three hours, with acetate additionally confirmed by NMR. But its Methods time-point experiment identifies pyruvate as a starting material, not a product generated under those conditions; the paper also does not establish significant production of every listed compound. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the presence of hydroxylamine and metallic iron under the same reaction conditions, four amino acids were also detected: glycine, alanine, aspartate and glutamate.
“In the presence of hydroxylamine, as a prebiotically plausible nitrogen source, and metallic iron (Fe0) under the same reaction conditions, four amino acids were also detected: glycine, alanine, aspartate and glutamate.”
From The protometabolic nature of prebiotic chemistry (2023) · cites this paper as [21]
Overall, this work has led to the formation of 9 out of 11 TCA intermediates and 5 universal metabolic precursors.
“Overall, this work has led to the formation of 9 out of 11 TCA intermediates and 5 universal metabolic precursors.”
From The protometabolic nature of prebiotic chemistry (2023) · cites this paper as [21]
Simulations can now be undertaken with geology and biology in mind, both in molecular dynamics and network biology, identifying constraints and parameters that can provide direction for experimental work.
“Simulations can now be undertaken with geology and biology in mind, both in molecular dynamics [22] and network biology [95,96], identifying constraints and parameters that can provide direction for experimental work [98,159,164].”
From The Future of Origin of Life Research: Bridging Decades-Old Divisions (2020) · cites this paper as [98]
The importance of relevant metals and metal clusters in the Hadean has settled in experimental work that recreates the origin of biochemistry in vitro, including carbon cycling, nitrogen fixation, ribosomal translation, and generation of pH gradients.
“In particular, the importance of relevant metals and metal clusters in the Hadean has settled in experimental work that recreates the origin of biochemistry in vitro, including carbon cycling [98,103,153], nitrogen fixation [154], ribosomal translation [155], and even the generation of pH gradients [156].”
From The Future of Origin of Life Research: Bridging Decades-Old Divisions (2020) · cites this paper as [98]
The data from Moran et al. revealed generation of a highly interconnected chemical pathway capable of both anabolic and catabolic activities by employing five main reaction mechanisms: oxidative and redox-neutral decarboxylation, reduction/oxidation, dehydration/hydration, and aldol/retro-aldol reactions.
“The data revealed the generation of a highly interconnected chemical pathway capable of both anabolic and catabolic activities by employing five main reaction mechanisms: oxidative and redox-neutral decarboxylation, reduction/oxidation, dehydration/hydration, and aldol/retro-aldol reactions.”
From Prebiotic Reaction Networks in Water (2020) · cites this paper as [23]
The resulting reaction network displayed significant resemblance to the TCA and glyoxylate cycles, containing 9 of 11 and 8 of 9 intermediates, respectively.
“The resulting reaction network was shown to display significant resemblance to the TCA and glyoxylate cycles, containing 9 of 11 and 8 of 9 intermediates, respectively.”
From Prebiotic Reaction Networks in Water (2020) · cites this paper as [23]
Moran and co-workers explored the capacity of iron to promote a (r-)TCA cycle analogue starting from glyoxylate and pyruvate.
“In 2019, Moran and co-workers [23] explored the capacity of iron to promote a (r-)TCA cycle analogue starting from glyoxylate 38 and pyruvate 39”
From Prebiotic Reaction Networks in Water (2020) · cites this paper as [23]
Iron was highly bioavailable during the early stages of the evolution of life, potentially rendering biochemistry irreversibly addicted to iron as a metallic cofactor.
“Furthermore, iron was highly bioavailable during the early stages of the evolution of life, potentially rendering biochemistry irreversibly ‘addicted’ to iron as a metallic cofactor. 4”
From The battle for iron in enteric infections (2020) · cites this paper as [4]
The rTCA cycle is an appealing candidate for early prebiotic metabolism because, similar to the oxidative TCA cycle, it produces the five universal precursors to biological metabolism.
“The rTCA cycle is an appealing candidate for early prebiotic metabolism because, similar to the oxidative TCA cycle, it produces the five universal precursors to biological metabolism (12, 14, 18).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [14]
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Cites
The Evolution and Future of Earth’s Nitrogen Cycle
Canfield, D. E., Glazer, A. N., & Falkowski, P. G. (2010) · Science · doi:10.1126/science.1186120 · Cited by 2,697 · see citing works
Prebiotic Systems Chemistry: New Perspectives for the Origins of Life
Ruiz-Mirazo, K., Briones, C., & de la Escosura, A. (2014) · Chemical Reviews · doi:10.1021/cr2004844 · Cited by 930 · see citing works
On the origin of biochemistry at an alkaline hydrothermal vent
Martin, W., & Russell, M. J. (2007) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2006.1881 · Cited by 771 · see citing works
Evolution of the first metabolic cycles.
Wächtershäuser, G. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.1.200 · Cited by 751 · see citing works
Iron Isotope Constraints on the Archean and Paleoproterozoic Ocean Redox State
Rouxel, O. J., Bekker, A., & Edwards, K. J. (2005) · Science · doi:10.1126/science.1105692 · Cited by 533 · see citing works
Universality in intermediary metabolism
Smith, E., & Morowitz, H. J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404922101 · Cited by 408 · see citing works
The search for the chemistry of life's origin
Eschenmoser, A. (2007) · Tetrahedron · doi:10.1016/j.tet.2007.10.012 · Cited by 292 · see citing works
Blueprint for a cell - the nature and origin of life
(1991) · Choice Reviews Online · doi:10.5860/choice.28-5078 · Cited by 273 · see citing works
The Implausibility of Metabolic Cycles on the Prebiotic Earth
Orgel, L. E. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060018 · Cited by 271 · see citing works
Non-Enzymatic Glycolysis and Pentose Phosphate Pathway-Like Reactions in a Plausible Archean Ocean
Keller, M. A., Turchyn, A. V., & Ralser, M. (2014) · Molecular Systems Biology · doi:10.1002/msb.20145228 · Cited by 242 · see citing works
Native iron reduces CO2 to intermediates and end-products of the acetyl-CoA pathway
Varma, S. J., Muchowska, K. B., Chatelain, P., & Moran, J. (2018) · Nature Ecology & Evolution · doi:10.1038/s41559-018-0542-2 · Cited by 235 · see citing works
Self-citationMetals promote sequences of the reverse Krebs cycle
Muchowska, K. B., Varma, S. J., Chevallot-Beroux, E., Lethuillier-Karl, L., Li, G., & Moran, J. (2017) · Nature Ecology & Evolution · doi:10.1038/s41559-017-0311-7 · Cited by 228 · see citing works
Self-citationRemnants of an Ancient Metabolism without Phosphate
Goldford, J. E., Hartman, H., Smith, T. F., & Segrè, D. (2017) · Cell · doi:10.1016/j.cell.2017.02.001 · Cited by 226 · see citing works
Opinion: Studies on the origin of life — the end of the beginning
Sutherland, J. D. (2017) · Nature Reviews Chemistry · doi:10.1038/s41570-016-0012 · Cited by 225 · see citing works
Bio-inspired CO 2 conversion by iron sulfide catalysts under sustainable conditions
Roldán, A., Hollingsworth, N., Roffey, A., Islam, H.-U., Goodall, J. B. M., Catlow, C. R. A., Darr, J. A., Bras, W., Sankar, G., Holt, K. B., et al. (2015) · Chemical Communications · doi:10.1039/c5cc02078f · Cited by 222 · see citing works
A primordial and reversible TCA cycle in a facultatively chemolithoautotrophic thermophile
Nunoura, T., Chikaraishi, Y., Izaki, R., Suwa, T., Sato, T., Harada, T., Mori, K., Kato, Y., Miyazaki, M., Shimamura, S., et al. (2018) · Science · doi:10.1126/science.aao3407 · Cited by 205 · see citing works
Vasas, V., Szathmáry, E., & Santos, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912628107 · Cited by 196 · see citing works
Reversibility of citrate synthase allows autotrophic growth of a thermophilic bacterium
Mall, A., Sobotta, J., Huber, C., Tschirner, C., Kowarschik, S., Bačnik, K., Mergelsberg, M., Boll, M., Hügler, M., Eisenreich, W., et al. (2018) · Science · doi:10.1126/science.aao2410 · Cited by 190 · see citing works
Speculations on the origin and evolution of metabolism
Hartman, H. (1975) · Journal of Molecular Evolution · doi:10.1007/bf01732537 · Cited by 187 · see citing works
The Compositional and Evolutionary Logic of Metabolism
Braakman, R., & Smith, E. (2012) · Physical Biology · doi:10.1088/1478-3975/10/1/011001 · Cited by 158 · see citing works
Iron catalysis at the origin of life
Camprubi, E., Jordan, S. F., Vasiliadou, R., & Lane, N. (2017) · IUBMB Life · doi:10.1002/iub.1632 · Cited by 144 · see citing works
Springsteen, G., Yerabolu, J. R., Nelson, J., Rhea, C. J., & Krishnamurthy, R. (2018) · Nature Communications · doi:10.1038/s41467-017-02591-0 · Cited by 132 · see citing works
Sulfate radicals enable a non-enzymatic Krebs cycle precursor
Keller, M. A., Kampjut, D., Harrison, S. A., & Ralser, M. (2017) · Nature Ecology & Evolution · doi:10.1038/s41559-017-0083 · Cited by 119 · see citing works
Prebiotic synthesis of phosphoenol pyruvate by α-phosphorylation-controlled triose glycolysis
Coggins, A. J., & Powner, M. W. (2017) · Nature Chemistry · doi:10.1038/nchem.2624 · Cited by 113 · see citing works
Driving Parts of Krebs Cycle in Reverse through Mineral Photochemistry
Zhang, X. V., & Martin, S. T. (2006) · Journal of the American Chemical Society · doi:10.1021/ja066103k · Cited by 106 · see citing works
Reactivity landscape of pyruvate under simulated hydrothermal vent conditions
Novikov, Y. Y., & Copley, S. D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1304923110 · Cited by 72 · see citing works
Life as a guide to prebiotic nucleotide synthesis
Harrison, S. A., & Lane, N. (2018) · Nature Communications · doi:10.1038/s41467-018-07220-y · Cited by 63 · see citing works
Modern views of ancient metabolic networks
Goldford, J. E., & Segrè, D. (2018) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2018.01.004 · Cited by 54 · see citing works
The Role of Aqueous Aerosols in the “Glyoxylate Scenario”: An Experimental Approach
Marín‐Yaseli, M. R., González‐Toril, E., Mompeán, C., & Ruiz‐Bermejo, M. (2016) · Chemistry - A European Journal · doi:10.1002/chem.201602195 · Cited by 48 · see citing works
Carbon Dioxide Fixation by Electrochemical Reduction in Water to Oxalate and Glyoxylate
Eggins, B. R., Brown, E. M., McNeill, E. A., & Grimshaw, J. (1988) · Tetrahedron Letters · doi:10.1016/s0040-4039(00)82489-2 · Cited by 43 · see citing works
Prebiotic synthesis of amino acids from formaldehyde and hydroxylamine in a modified sea medium
Sakurai, M., & Yanagawa, H. (1984) · Origins of Life and Evolution of Biospheres · doi:10.1007/bf00933655 · Cited by 29 · see citing works
Cavitation-Induced Synthesis of Biogenic Molecules on Primordial Earth
Kalson, N.-H., Furman, D., & Yehuda Zeiri, B. (2017) · ACS Central Science · doi:10.1021/acscentsci.7b00325 · Cited by 29 · see citing works
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Regulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535 · see citing works
“Intriguingly, certain reaction sequences of the cycle have been shown to occur nonenzymatically in the presence of minerals under UV radiation or using metal ions under acidic and aqueous conditions, not unlike those proposed on early Earth (12, 14, 19, 20).”
BackgroundInfluentialNonenzymatic Metabolic Reactions and Life’s Origins
Muchowska, K. B., Varma, S. J., & Moran, J. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00191 · Cited by 317 · see citing works
Self-citationUnified Prebiotically Plausible Synthesis of Pyrimidine and Purine RNA Ribonucleotides
Becker, S., Feldmann, J., Wiedemann, S., Okamura, H., Schneider, C., Iwan, K., Crisp, A., Rossa, M., Amatov, T., & Carell, T. (2019) · Science · doi:10.1126/science.aax2747 · Cited by 306 · see citing works
Autocatalytic chemical networks at the origin of metabolism
Xavier, J. C., Hordijk, W., Kauffman, S., Steel, M., & Martin, W. F. (2020) · Proceedings of the Royal Society B: Biological Sciences · doi:10.1098/rspb.2019.2377 · Cited by 196 · see citing works
The Future of Origin of Life Research: Bridging Decades-Old Divisions
Preiner, M., Asche, S., Becker, S., Betts, H. C., Boniface, A., Camprubi, E., Chandru, K., Erastova, V., Garg, S. G., Khawaja, N., et al. (2020) · Life · doi:10.3390/life10030020 · Cited by 140 · see citing works
Self-citationOlder than genes: the acetyl CoA pathway and origins
Martin, W. F. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00817 · Cited by 132 · see citing works
A prebiotic basis for ATP as the universal energy currency
Pinna, S., Kunz, C., Halpern, A., Harrison, S. A., Jordan, S. F., Ward, J., Werner, F., & Lane, N. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001437 · Cited by 103 · see citing works
Pulletikurti, S., Yadav, M., Springsteen, G., & Krishnamurthy, R. (2022) · Nature Chemistry · doi:10.1038/s41557-022-00999-w · Cited by 78 · see citing works
The ambivalent role of water at the origins of life
do Nascimento Vieira, A., Kleinermanns, K., Martin, W. F., & Preiner, M. (2020) · FEBS Letters · doi:10.1002/1873-3468.13815 · Cited by 73 · see citing works
Beyazay, T., Belthle, K. S., Farès, C., Preiner, M., Moran, J., Martin, W. F., & Tüysüz, H. (2023) · Nature Communications · doi:10.1038/s41467-023-36088-w · Cited by 72 · see citing works
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Sousa Gerós, A., Simmons, A., Drakesmith, H., Aulicino, A., & Frost, J. N. (2020) · Immunology · doi:10.1111/imm.13236 · Cited by 58 · see citing works
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Schmitt-Kopplin, P., Hemmler, D., Moritz, F., Gougeon, R. D., Lucio, M., Meringer, M., Müller, C., Harir, M., & Hertkorn, N. (2019) · Faraday Discussions · doi:10.1039/c9fd00078j · Cited by 60 · see citing works
The protometabolic nature of prebiotic chemistry
Nogal, N., Sanz-Sánchez, M., Vela-Gallego, S., Ruiz-Mirazo, K., & de la Escosura, A. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00594a · Cited by 61 · see citing works
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Yadav, M., Pulletikurti, S., Yerabolu, J. R., & Krishnamurthy, R. (2022) · Nature Chemistry · doi:10.1038/s41557-021-00878-w · Cited by 48 · see citing works
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Bizzarri, B. M., Saladino, R., Delfino, I., García-Ruiz, J. M., & Di Mauro, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020917 · Cited by 33 · see citing works
Miao, X., Paikar, A., Lerner, B., Diskin‐Posner, Y., Shmul, G., & Semenov, S. N. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202105790 · Cited by 20 · see citing works
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- Authors
- Muchowska, K. B., Varma, S. J., & Moran, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Moran, Joseph
- Venue
- Nature
- Published
- 2019-05-01
- Volume
- 569
- Issue
- 7754
- Pages
- 104-107
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6517266
- OpenAlex
- W2942743302
- Cited by
- 365
- References
- 32
- Citations by year
- 2026: 36 · 2025: 52 · 2024: 47 · 2023: 38 · 2022: 62 · 2021: 59 · 2020: 45 · 2019: 24 · 2018: 1
- FWCI
- 25.36
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-04-17)
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Royal College of Surgeons in Ireland (submittedVersion, cc-by-nc-nd)
- Funders
- European Commission (HORIZON2020)
- Agence Nationale de la Recherche (ANR-10LABX-0026CSC, ANR-10-LABX-0026, ANR-10)
- China Scholarship Council
- H2020 European Research Council (639170)
- Topics
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- origin of metabolism, prebiotic chemistry, TCA cycle, glyoxylate cycle, pyruvate, glyoxylic acid, CO2 reduction, amino acid synthesis, hydroxylamine, anabolism and catabolism
- MeSH terms
- Carbon Dioxide, Citric Acid Cycle, Ferrous Compounds, Glyoxylates, Iron, Pyruvic Acid, Hydroxylamine, Metabolic Networks and Pathways
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