Life is an out-of-equilibrium system sustained by a continuous supply of energy. In extant biology, the generation of the primary energy currency, adenosine 5′-triphosphate and its use in the synthesis of biomolecules require enzymes. Before their emergence, alternative energy sources, perhaps assisted by simple catalysts, must have mediated the activation of carboxylates and phosphates for condensation reactions. Here, we show that the chemical energy inherent to isonitriles can be harnessed to activate nucleoside phosphates and carboxylic acids through catalysis by acid and 4,5-dicyanoimidazole under mild aqueous conditions. Simultaneous activation of carboxylates and phosphates provides multiple pathways for the generation of reactive intermediates, including mixed carboxylic acid–phosphoric acid anhydrides, for the synthesis of peptidyl–RNAs, peptides, RNA oligomers and primordial phospholipids. Our results indicate that unified prebiotic activation chemistry could have enabled the joining of building blocks in aqueous solution from a common pool and enabled the progression of a system towards higher complexity, foreshadowing today’s encapsulated peptide–nucleic acid system.
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All data generated or analysed during this study are included in the manuscript and the Supplementary Information.
Verlander, M. S., Lohrmann, R. & Orgel, L. E. Catalysts for the self-polymerization of adenosine cyclic 2′,3′-phosphate. J. Mol. Evol. 2, 303–316 (1973).
Lambert, J.-F. Adsorption and polymerization of amino acids on mineral surfaces: A review. Orig. Life Evol. Biosph. 38, 211–242 (2008).
Kanavarioti, A., Monnard, P.-A. & Deamer, D. W. Eutectic phase in ice facilitate nonenzymatic nucleic acid synthesis. Astrobiology 1, 271–281 (2001).
Canavelli, P., Islam, S. & Powner, M. Peptide ligation by chemoselective aminonitrile coupling in water. Nature 571, 546–549 (2019).
Lohrmann, R. & Orgel, L. E. Prebiotic synthesis: phosphorylation in aqueous solution. Science 161, 64–66 (1968).
Ibanez, J. D., Kimball, A. P. & Oró, J. Possible prebiotic condensation of mononucleotides by cyanamide. Science 173, 444–446 (1971).
Leman, L., Orgel, L. E. & Ghadiri, M. R. Carbonyl sulfide-mediated prebiotic formation of peptides. Science 306, 283–286 (2004).
Leman, L., Orgel, L. E. & Ghadiri, M. R. Amino acid dependent formation of phosphate anhydrides in water mediated by carbonyl sulfide. J. Am. Chem. Soc. 128, 20–21 (2006).
Tsanakopoulou, M. & Sutherland, J. D. Cyanamide as a prebiotic phosphate activating agent – catalysis by simple 2-oxoacid salts. Chem. Commun. 53, 11893–11896 (2017).
Liu, Z. et al. Tuning the reactivity of nitriles using Cu(ii) catalysis – potentially prebiotic activation of nucleotides. Chem. Sci. 9, 7053–7057 (2018).
Orgel, L. E. Evolution of the genetic apparatus. J. Mol. Biol. 38, 381–393 (1968).
Remijan, A. J., Hollis, J. M., Lovas, F. J., Plusquellic, D. F. & Jewell, P. R. Interstellar isomers: the importance of bonding energy differences. Astrophys. J. 632, 333–339 (2005).
Xiang, Y.-B., Drenkard, S., Baumann, K., Hickey, D. & Eschenmoser, A. Chemie von α-aminonitrilen 12. Mitteilung. Sondierungen über thermische umwandlungen von α-aminonitrilen. Helv. Chim. Acta 77, 2209–2250 (1994).
Xu, J. et al. Photochemical reductive homologation of hydrogen cyanide using sulfite and ferrocyanide. Chem. Commun. 54, 5566–5569 (2018).
Mariani, A., Russell, D. A., Javelle, T. & Sutherland, J. D. A light-releasable potentially prebiotic nucleotide activating agent. J. Am. Chem. Soc. 140, 8657–8661 (2018).
Mullen, L. B. & Sutherland, J. D. Simultaneous nucleotide activation and synthesis of amino acid amides by a potentially prebiotic multi-component reaction. Angew. Chem. Int. Ed. 46, 8063–8066 (2007).
Pirrung, M. C. & Sarma, K. D. Multicomponent reactions are accelerated in water. J. Am. Chem. Soc. 126, 444–445 (2004).
Paprocki, D., Koszelewski, D., Walde, P. & Ostaszewski, R. Efficient Passerini reactions in an aqueous vesicle system. RSC Adv. 5, 102828–102835 (2015).
Sung, K. & Chen, C.-C. Kinetics and mechanism of acid-catalysed hydrolysis of cyclohexyl isonitrile and pKa determination of N-cyclohexylnitrilium ion. Tetrahedron Lett. 42, 4845–4848 (2001).
Lim, Y.-Y. & Stein, A. R. Acid-catalysed solvolysis of isonitriles. I. Can. J. Chem. 49, 2455–2459 (1971).
Biron, J., Parkes, A., Pascal, R. & Sutherland, J. D. Expeditious, potentially primordial, aminoacylation of nucleotides. Angew. Chem. Int. Ed. 117, 6889–6892 (2005).
Bowler, F. R. et al. Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation. Nat. Chem. 5, 383–389 (2013).
Jencks, W. P. & Carriuolo, J. Imidazole catalysis. II. Acyl transfer and the reactions of acetyl imidazole with water and oxygen anions. J. Biol. Chem. 234, 1272–1279 (1959).
Lacey, J. C. Jr. & White, W. E. Jr. Aminoacyl transfer: chemical conversion of an aminoacyl adenylate to an imidazolide. Biochem. Biophys. Res. Commun. 47, 565–573 (1972).
Ferris, J. P. & Kuder, J. E. Chemical evolution. III. The photochemical conversion of enaminonitriles to imidazoles. J. Am. Chem. Soc. 92, 2527–2533 (1970).
Oró, J. & Kimball, A. P. Synthesis of purines under possible primitive earth conditions. I. Adenine from hydrogen cyanide. Arch. Biochem. Biophys. 94, 217–227 (1961).
Fahrenbach, A. et al. Common and potentially prebiotic origin for precursors of nucleotide synthesis and activation. J. Am. Chem. Soc. 139, 8780–8783 (2017).
Hudson, J. S. et al. A unified mechanism for abiotic adenine and purine synthesis in formamide. Angew. Chem. Int. Ed. 51, 5134–5137 (2012).
Mariani, A. & Sutherland, J. D. Non-enzymatic RNA backbone proofreading through energy-dissipative recycling. Angew. Chem. Int. Ed. 56, 6563–6566 (2017).
Danger, G. et al. 5(4H)‐Oxazolones as intermediates in the carbodiimide‐ and cyanamide‐promoted peptide activations in aqueous solution. Angew. Chem. Int. Ed. 52, 611–614 (2013).
Liu, Z., Beaufils, D., Rossi, J. & Pascal, R. Evolutionary importance of the intramolecular pathways of hydrolysis of phosphate ester mixed anhydrides with amino acids and peptides. Sci. Rep. 4, 7440 (2014).
Liu, Z., Rigger, L., Rossi, J., Sutherland, J. D. & Pascal, R. Mixed anhydride intermediates in the reaction of 5(4H)‐oxazolones with phosphate esters and nucleotides. Chem. Eur. J. 22, 14940–14949 (2016).
Tamura, K. & Schimmel, P. R. Chiral-selective aminoacylation of an RNA minihelix. Science 305, 1253 (2004).
Tamura, K. & Schimmel, P. R. Chiral-selective aminoacylation of an RNA minihelix: mechanistic features and chiral suppression. Proc. Natl Acad. Sci. USA 103, 13750–13752 (2006).
Beaufils, D., Jepaul, S., Liu, Z., Boiteau, L. & Pascal, R. The activation of free dipeptides promoted by strong activating agents in water does not yield diketopiperazines. Orig. Life Evol. Biosph. 46, 19–30 (2016).
Patel, B. H., Percivalle, C., Ritson, D. J., Duffy, C. D. & Sutherland, J. D. Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nat. Chem. 7, 301–307 (2015).
Gibard, C., Bhowmik, S., Karki, M., Kim, E.-K. & Krishnamurthy, R. Phosphorylation, oligomerization and self-assembly in water under potential prebiotic conditions. Nat. Chem. 10, 212–217 (2018).
Bonfio, C. et al. Length-selective synthesis of diacylglycerol-phosphates through energy-dissipative cycling. J. Am. Chem. Soc. 141, 3934–3939 (2019).
Sutherland, J. D. The origin of life—out of the blue. Angew. Chem. Int. Ed. 55, 104–121 (2016).
Lorenz, M. R. et al. Proton gradients and pH oscillations emerge from heat flow at the microscale. Nat. Commun. 8, 1897 (2017).
Cech, T. R. Evolution of biological catalysis: ribozyme to RNP enzyme. Cold Spring Harbor Symp. Quant. Biol. 74, 11–16 (2009).
Hein, J. E., Tse, E. & Blackmond, D. G. A route to enantiopure RNA precursors from nearly racemic starting materials. Nat. Chem. 3, 704–706 (2011).
Blain, J. C. & Szostak, J. W. Progress towards synthetic cells. Annu. Rev. Biochem. 83, 615–640 (2014).
Sutherland, J. D. Opinion: Studies on the origin of life – the end of the beginning. Nat. Rev. Chem. 1, 0012 (2017).
Sheehan, J. C. & Yang, D.-D. H. The use of N-formyl amino acids in peptide synthesis. J. Am. Chem. Soc. 80, 1154–1158 (1958).
Kim, K.-H., Martin, Y., Otis, E. & Mao, J. Inhibition of iodine-125 labeled ristocetin binding to Micrococcus luteus cells by the peptides related to bacterial cell wall mucopeptide precursors: quantitative structure–activity relationships. J. Med. Chem. 32, 84–93 (1989).
This research was supported by the Medical Research Council (no. MC_UP_A024_1009 to J.D.S.) and the Simons Foundation (no. 290362 to J.D.S.). We thank all J.D.S. group members for fruitful discussions. We thank R. Pascal for helpful suggestions.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Liu, Z., Wu, LF., Xu, J. et al. Harnessing chemical energy for the activation and joining of prebiotic building blocks. Nat. Chem. 12, 1023–1028 (2020). https://doi.org/10.1038/s41557-020-00564-3
Nature Chemistry (2021)
Nature Reviews Chemistry (2021)
Scientific Reports (2021)
Nature Chemistry (2020)