Cyanide as a primordial reductant enables a protometabolic reductive glyoxylate pathway
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Abstract
Investigation of prebiotic metabolic pathways is predominantly based on abiotically replicating the reductive citric acid cycle. While attractive from a parsimony point of view, attempts using metal/mineral-mediated reductions have produced complex mixtures with inefficient and uncontrolled reactions. Here we show that cyanide acts as a mild and efficient reducing agent mediating abiotic transformations of tricarboxylic acid intermediates and derivatives. The hydrolysis of the cyanide adducts followed by their decarboxylation enables the reduction of oxaloacetate to malate and of fumarate to succinate, whereas pyruvate and α-ketoglutarate themselves are not reduced. In the presence of glyoxylate, malonate and malononitrile, alternative pathways emerge that bypass the challenging reductive carboxylation steps to produce metabolic intermediates and compounds found in meteorites. These results suggest a simpler prebiotic forerunner of today's metabolism, involving a reductive glyoxylate pathway without oxaloacetate and α-ketoglutarate-implying that the extant metabolic reductive carboxylation chemistries are an evolutionary invention mediated by complex metalloproteins.
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Cites
Before enzymes and templates: theory of surface metabolism
Wächtershäuser, G. (1988) · Microbiological Reviews · doi:10.1128/mmbr.52.4.452-484.1988 · Cited by 1,242 · see citing works
Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism
Patel, B. H., Percivalle, C., Ritson, D. J., Duffy, C. D., & Sutherland, J. D. (2015) · Nature Chemistry · doi:10.1038/nchem.2202 · Cited by 949 · see citing works
Primordial Carbonylated Iron-Sulfur Compounds and the Synthesis of Pyruvate
Cody, G. D., Boctor, N. Z., Filley, T. R., Hazen, R. M., Scott, J. H., Sharma, A., & Yoder, H. S. (2000) · Science · doi:10.1126/science.289.5483.1337 · Cited by 441 · see citing works
The Origin of Life—Out of the Blue
Sutherland, J. D. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201506585 · Cited by 401 · see citing works
Synthesis and breakdown of universal metabolic precursors promoted by iron
Muchowska, K. B., Varma, S. J., & Moran, J. (2019) · Nature · doi:10.1038/s41586-019-1151-1 · Cited by 365 · see citing works
HCN and chemical evolution: The possible role of cyano compounds in prebiotic synthesis
Ferris, J. P., & Hagan, W. J. (1984) · Tetrahedron · doi:10.1016/s0040-4020(01)99315-9 · Cited by 354 · see citing works
The origin of intermediary metabolism
Morowitz, H. J., Kostelnik, J. D., Yang, J. J., & Cody, G. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.110153997 · Cited by 338 · see citing works
Nonenzymatic 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
The Organic Composition of Carbonaceous Meteorites: The Evolutionary Story Ahead of Biochemistry
Pizzarello, S., & Shock, E. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a002105 · Cited by 285 · 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
Living with Iron (and Oxygen): Questions and Answers about Iron Homeostasis
Theil, E. C., & Goss, D. J. (2009) · Chemical Reviews · doi:10.1021/cr900052g · Cited by 265 · see citing works
Prebiotic Synthesis of Simple Sugars by Photoredox Systems Chemistry
Ritson, D., & Sutherland, J. D. (2012) · Nature Chemistry · doi:10.1038/nchem.1467 · Cited by 258 · see citing works
The Chemistry of Life's Origin: A Carbonaceous Meteorite Perspective
Pizzarello, S. (2006) · Accounts of Chemical Research · doi:10.1021/ar050049f · Cited by 253 · see citing works
Chemistry of potentially prebiological natural products
Eschenmoser, A., & Loewenthal, E. (1992) · Chemical Society Reviews · doi:10.1039/cs9922100001 · Cited by 245 · 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
On the Origin of Metabolic Pathways
Lazcano, A., & Miller, S. L. (1999) · Journal of Molecular Evolution · doi:10.1007/pl00006565 · Cited by 219 · 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
Prebiotic synthesis of cysteine peptides that catalyze peptide ligation in neutral water
Foden, C. S., Islam, S., Fernández-García, C., Maugeri, L., Sheppard, T. D., & Powner, M. W. (2020) · Science · doi:10.1126/science.abd5680 · Cited by 205 · see citing works
Freeman, F. (1969) · Chemical Reviews · doi:10.1021/cr60261a001 · Cited by 200 · see citing works
Ribozyme Catalysis of Metabolism in the RNA World
Chen, X., Li, N., & Ellington, A. D. (2007) · Chemistry & Biodiversity · doi:10.1002/cbdv.200790055 · 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 192 · see citing works
High CO2 levels drive the TCA cycle backwards towards autotrophy
Steffens, L., Pettinato, E., Steiner, T. M., Mall, A., König, S., Eisenreich, W., & Berg, I. A. (2021) · Nature · doi:10.1038/s41586-021-03456-9 · Cited by 191 · see citing works
Peptide ligation by chemoselective aminonitrile coupling in water
Canavelli, P., Islam, S., & Powner, M. W. (2019) · Nature · doi:10.1038/s41586-019-1371-4 · Cited by 188 · see citing works
The glyoxylate shunt, 60 years on
Dolan, S. K., & Welch, M. (2018) · Annual Review of Microbiology · doi:10.1146/annurev-micro-090817-062257 · Cited by 180 · 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
Self-citationCooper, G., Reed, C., Nguyen, D. T., Carter, M., & Wang, Y. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105715108 · Cited by 131 · see citing works
Cody, G. D., Boctor, N. Z., Hazen, R. M., Brandes, J. A., Morowitz, H. J., & Yoder, H. S. (2001) · Geochimica et Cosmochimica Acta · doi:10.1016/s0016-7037(01)00674-3 · Cited by 130 · 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 121 · see citing works
A plausible metal-free ancestral analogue of the Krebs cycle composed entirely of α-ketoacids
Stubbs, R. T., Yadav, M., Krishnamurthy, R., & Springsteen, G. (2020) · Nature Chemistry · doi:10.1038/s41557-020-00560-7 · Cited by 117 · see citing works
Self-citationPrebiotic 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
The TNA-Family of Nucleic Acid Systems: Properties and Prospects
Eschenmoser, A. (2004) · Origins of Life and Evolution of Biospheres · doi:10.1023/b:orig.0000016450.59665.f4 · Cited by 89 · see citing works
Grönberg, K. L. C., Gormal, C. A., Durrant, M. C., et al. (1998) · Journal of the American Chemical Society · doi:10.1021/ja981832o · Cited by 88 · see citing works
Life’s Biological Chemistry: A Destiny or Destination Starting from Prebiotic Chemistry?
Krishnamurthy, R. (2018) · Chemistry – A European Journal · doi:10.1002/chem.201801847 · Cited by 76 · see citing works
Self-citationA reverse glyoxylate shunt to build a non-native route from C4 to C2 in Escherichia coli
Mainguet, S. E., Gronenberg, L. S., Wong, S. S., & Liao, J. C. (2013) · Metabolic Engineering · doi:10.1016/j.ymben.2013.06.004 · Cited by 72 · see citing works
Spectroscopic Evidence of Keto−Enol Tautomerism in Deliquesced Malonic Acid Particles
Ghorai, S., Laskin, A., & Tivanski, A. V. (2011) · The Journal of Physical Chemistry A · doi:10.1021/jp112360x · Cited by 66 · see citing works
Prebiotic photoredox synthesis from carbon dioxide and sulfite
Liu, Z., Wu, L.-F., Kufner, C. L., Sasselov, D. D., Fischer, W. W., & Sutherland, J. D. (2021) · Nature Chemistry · doi:10.1038/s41557-021-00789-w · Cited by 66 · see citing works
Sugimoto, N., Engelgau, P., Jones, A. D., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009988118 · Cited by 64 · 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
Guzmán, M. I., & Martin, S. T. (2010) · Chemical Communications · doi:10.1039/b924179e · Cited by 56 · 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
Kinetic Challenges Facing Oxalate, Malonate, Acetoacetate, and Oxaloacetate Decarboxylases
Wolfenden, R. V., Lewis, C. A., & Yuan, Y. Z. (2011) · Journal of the American Chemical Society · doi:10.1021/ja111457h · Cited by 47 · see citing works
Butch, C., Cope, E. D., Pollet, P., Gelbaum, L., Krishnamurthy, R., & Liotta, C. L. (2013) · Journal of the American Chemical Society · doi:10.1021/ja405103r · Cited by 46 · see citing works
Self-citationKunz, D. A., Chen, J., & Pan, G. (1998) · Applied and Environmental Microbiology · doi:10.1128/aem.64.11.4452-4459.1998 · Cited by 46 · see citing works
Russell, J. B., & Forsberg, N. E. (1986) · British Journal Of Nutrition · doi:10.1079/bjn19860095 · Cited by 40 · see citing works
Fay, A. W., Blank, M. A., Yoshizawa, J., et al. (2010) · Dalton Transactions · doi:10.1039/c000264j · Cited by 27 · see citing works
Equilibrium, kinetics, and mechanism of the malonic acid–iodine reaction
Leopold, K. R., & Haim, A. (1977) · International Journal of Chemical Kinetics · doi:10.1002/kin.550090108 · Cited by 26 · see citing works
Carbon–Metal Bonds: Rare and Primordial in Metabolism
Martin, W. F. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.04.010 · Cited by 23 · see citing works
Colín-García, M., Negrón-Mendoza, A., & Ramos-Bernal, S. (2009) · Astrobiology · doi:10.1089/ast.2006.0117 · Cited by 22 · see citing works
Krishnamurthy, R., Liotta, C. L., Mohammed, F. S., Chen, K., Mojica, M. A., Conley, M., Napoline, J. W., Butch, C. J., & Pollet, P. (2016) · Synlett · doi:10.1055/s-0036-1588657 · Cited by 22 · see citing works
Self-citationThe Power Without the Glory: Multiple Roles of Hydrogen Peroxide in Mediating the Origin of Life
Ball, R. V., & Brindley, J. (2019) · Astrobiology · doi:10.1089/ast.2018.1886 · Cited by 22 · see citing works
A cyanosulfidic origin of the Krebs cycle
Ritson, D. J. (2021) · Science Advances · doi:10.1126/sciadv.abh3981 · Cited by 21 · see citing works
The Viability of a Nonenzymatic Reductive Citric Acid Cycle – Kinetics and Thermochemistry
Ross, D. S. (2006) · Origins of Life and Evolution of Biospheres · doi:10.1007/s11084-006-9017-6 · Cited by 20 · see citing works
Yerabolu, J. R., Liotta, C. L., & Krishnamurthy, R. (2017) · Chemistry - A European Journal · doi:10.1002/chem.201701497 · Cited by 16 · see citing works
Self-citationSutter's Mill dicarboxylic acids as possible tracers of parent‐body alteration processes
Pizzarello, S., & Garvie, L. A. J. (2014) · Meteoritics and Planetary Science · doi:10.1111/maps.12264 · Cited by 15 · see citing works
Carbon Acidity in Enzyme Active Sites
Toney, M. D. (2019) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2019.00025 · Cited by 13 · see citing works
Bender, M. L., & Connors, K. A. (1962) · Journal of the American Chemical Society · doi:10.1021/ja00869a041 · Cited by 11 · see citing works
Addition reactions of malonic nitriles with alkanethiol in aqueous solution
Raulin, F., Bloch, S., & Toupance, G. (1977) · Origins of Life and Evolution of Biospheres · doi:10.1007/bf00930686 · Cited by 11 · see citing works
Reactivity of Metabolic Intermediates and Cofactor Stability under Model Early Earth Conditions
Maltais, T. R., VanderVelde, D. G., LaRowe, D. E., Goldman, A. D., & Barge, L. M. (2020) · Origins of Life and Evolution of Biospheres · doi:10.1007/s11084-019-09590-9 · Cited by 11 · see citing works
The Abiotic Oxidation of Organic Acids to Malonate
Springsteen, G., Rice, G., Yerabolu, J., & Krishnamurthy, R. (2016) · Synlett · doi:10.1055/s-0036-1588649 · Cited by 5 · 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
“However, demonstration of the C-C bond forming reactions of the rTCA cycle has yet to be achieved efficiently and nonenzymatically under experimental conditions, raising the possibility that this portion of the pathway required organic catalysts and, thus, emerged later (21, 22).”
BackgroundPulletikurti, S., Yadav, M., Springsteen, G., & Krishnamurthy, R. (2022) · Nature Chemistry · doi:10.1038/s41557-022-00999-w · Cited by 78 · see citing works
Self-citationThe 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
- Authors
- Yadav, M., Pulletikurti, S., Yerabolu, J. R., & Krishnamurthy, R.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Krishnamurthy, Ramanarayanan
- Venue
- Nature Chemistry
- Published
- 2022-02
- Volume
- 14
- Issue
- 2
- Pages
- 170-178
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- OpenAlex
- W4225886185
- Cited by
- 48
- References
- 59
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 15 · 2023: 5 · 2022: 11
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Chemistry (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Aeronautics and Space Administration (80NSSC181300, 80NSSC18K1300)
- NSF | Directorate for Mathematical & Physical Sciences | Division of Chemistry (CHE-1504217)
- Simons Foundation (32712FY19)
- Topics
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Space Science and Extraterrestrial Life
- Keywords
- cyanide, prebiotic metabolism, reductive carboxylation, TCA cycle, fumarate reduction, malononitrile, malonate, origin of metabolism, metalloproteins
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