Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides

Abstract

The nature of the first genetic polymer is the subject of major debate1. Although the ‘RNA world’ theory suggests that RNA was the first replicable information carrier of the prebiotic era—that is, prior to the dawn of life2,3—other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA4. Such a theory streamlines the eventual ‘genetic takeover’ of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life5.

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Fig. 1: Previous synthesis of RNA pyrimidine nucleosides C (1), U (2) and a deoxypyrimidine nucleoside (5), and the present work.
Fig. 2: Prebiotic route to purine deoxyribonucleosides, 7 (dA) and 9 (dI).
Fig. 3: Proposed mechanism of photoreduction of N7-8,2′-anhydro-thioadenosine (18) and N9-8,2′-anhydro-thioadenosine (19) nucleosides.
Fig. 4: A systems-level approach to a potential primordial genetic alphabet composed of 1 (C), 2 (U), 7 (dA) and 9 (dI).

Data and materials availability

The Supplementary Information available for this Article contains all procedures, characterization data, NMR spectra, HPLC traces, X-ray data and Cambridge Crystallographic Data Centre (CCDC) numbers, plus theoretical methods and data. Any additional data are available from the corresponding author upon reasonable request.

Code availability

All custom code used to generate the data in this study is available upon reasonable request.

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Acknowledgements

The authors thank all JDS group members for discussions. This research was supported by the Medical Research Council (MC_UP_A024_1009), the Simons Foundation (290362 to J.D.S., 494188 to R.S.), and a grant from the National Science Centre Poland (2016/23/B/ST4/01048 to R.W.G.). M.J.J. acknowledges the support of the ‘Diamond Grant’ (0144/DIA/2017/46) from the Polish Ministry of Science and Higher Education and a computational grant from Wrocław Centre of Networking and Supercomputing (WCSS). R.S. thanks the Foundation for Polish Science for support from the START Fellowship.

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Experimental contributions by J.X., V.C., N.J.G., D.A.R. and A.D.B. Theoretical contributions by M.J.J., R.W.G. and R.S. Crystallography by A.D.B. This work was supervised by J.D.S. All authors co-wrote the manuscript.

Corresponding author

Correspondence to John D. Sutherland.

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Peer review information Nature thanks Hannes Mutschler and Yitzhak Tor for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 A summary of the main findings of the work.

Previously, a prebiotically plausible synthesis of β-ribopyrimdines C and U has been identified using α-thiocytidine. Herein, we demonstrate that the same intermediate can undergo a distinct prebiotically plausible process that could have happened in a similar—or the same—environment. This process furnishes β-D-N9-deoxyribopurine nucleosides dA and dI alongside the pyrimidines. Remarkable selectivity enforced by UV irradiation and hydrolysis operates throughout the reported ribosylpyrimidine synthesis and the discovered deoxyribosylpurine synthesis, resulting in a set of nucleosides with only the canonical regio- and stereochemistry. The coexistence in one location of a set of nucleosides similar to this is thought to be a precondition for the spontaneous emergence of life on Earth6,47.

Extended Data Fig. 2 1H NMR spectra of conversion of α-anhydrouridine (15) from α-thiouridine (14).

a, 1H NMR spectrum of 15. b, 1H NMR spectrum of the reaction mixture after heating 14 in H2O. c, 1H NMR spectrum of the reaction mixture after heating 14 in formamide. f1, chemical shift (δ).

Extended Data Fig. 3 1H NMR spectra of photoreduction of N7-8,2′-anhydro-thioadenosine (18) and N9-8,2′-anhydro-thioadenosine (19) mixture with bisulfite.

a, 1H NMR spectrum of the crude mixture before irradiation; the ratio of N7:N9 isomer was 4:5. b, 1H NMR spectrum of the mixture after irradiation for 7 h; the N9 isomers dA (7) and 26 are the only detectable products. f1, chemical shift (δ).

Extended Data Fig. 4 Potential energy surfaces and S1/S0 state crossings of the key photochemical steps in deoxyadenosine synthesis calculated using ADC(2) and the ma-def2-TZVP basis set.

See Supplementary Information for details. a, Potential energy profile of UV-induced C–S bond scission of 18. C–S bond opening may spontaneously occur in 18, leading to a peaked S1/S0 state crossing; however, a reducing agent is necessary to maintain that geometry after reaching the S0 state. b, Potential energy profile of UV-induced N7–C8 bond scission of 19 . N7–C8 bond rupture is the lowest-energy photochemical process in 19 and results in destruction of the purine ring. c, d, Potential energy profiles of the UV-induced C–S bond scission of encounter complexes 18 (c) and 19 (d) with HS. Photochemical C–S bond rupture induced by charge transfer from HS to a chromophore and is a barrierless process.

Extended Data Fig. 5 Equilibrium geometries of C2, S8 radical anion (31) and C8, N9 radical anion (32).

Radical anions may be formed after accepting a hydrated electron from the environment. The adiabatic electron affinities are calculated using ωB97X-D/IEFPCM and the ma-def2-TZVP basis set.

Extended Data Fig. 6 1H NMR spectra for the reactions of deoxyadenosine (dA, 7) and cytidine (C, 1) with nitrous acid.

a, 1H NMR spectrum of the mixture of dA (7) and C (1). b, 1H NMR spectrum of the reaction mixture after 4 d, showing that the ratio of the four (deoxy)nucleosides dA (7), deoxyinosine (dI, 9), C (1), and uridine (U, 2) is 30:17:42:11. f1, chemical shift (δ).

Extended Data Fig. 7 1H NMR spectra for stability study of cytidine (C; 1) and uridine (U; 2) at 254 nm irradiation with bisulfite.

a, 1H NMR spectrum of the mixture of C (1), bisulfite and K4Fe(CN)6 in the dark. b, As in a, after 10 h of irradiation. c, 1H NMR spectrum of the mixture of U (2), bisulfite and K4Fe(CN)6 in the dark. d, As in c, after 10 h of irradiation. e, 1H NMR spectrum of the mixture of C (1), U (2), N9-thioanhydroadenosine (18), bisulfite and K4Fe(CN)6 in the dark. f, As in e, after 10 h of irradiation. f1, chemical shift (δ).

Extended Data Fig. 8 1H NMR spectra for sequential reactions with the mixture of α-anhydrouridine (15), C (1) and U (2).

a, 1H NMR spectrum of the mixture after heating with 8-mercaptoadenine (16) and magnesium chloride at 150 °C for 1.5 d. b, As in a, after irradiation with hydrogen sulfide at 254 nm. c, As in a, after reacting with nitrous acid for 2 d; dA (7):dI (9):C (1):U (2) = 14:14:44:28). f1, chemical shift (δ).

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Xu, J., Chmela, V., Green, N. et al. Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides. Nature 582, 60–66 (2020). https://doi.org/10.1038/s41586-020-2330-9

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