Prebiotic phosphorylation of 2-thiouridine provides either nucleotides or DNA building blocks via photoreduction

Abstract

Breakthroughs in the study of the origin of life have demonstrated how some of the building blocks essential to biology could have been formed under various primordial scenarios, and could therefore have contributed to the chemical evolution of life. Missing building blocks are then sometimes inferred to be products of primitive biosynthesis, which can stretch the limits of plausibility. Here, we demonstrate the synthesis of 2′-deoxy-2-thiouridine, and subsequently 2′-deoxyadenosine and 2-deoxyribose, under prebiotic conditions. 2′-Deoxy-2-thiouridine is produced by photoreduction of 2,2′-anhydro-2-thiouridine, which is in turn formed by phosphorylation of 2-thiouridine—an intermediate of prebiotic RNA synthesis. 2′-Deoxy-2-thiouridine is an effective deoxyribosylating agent and may have functioned as such in either abiotic or proto-enzyme-catalysed pathways to DNA, as demonstrated by its conversion to 2′-deoxyadenosine by reaction with adenine, and 2-deoxyribose by hydrolysis. An alternative prebiotic phosphorylation of 2-thiouridine leads to the formation of its 5′-phosphate, showing that hypotheses in which 2-thiouridine was a key component of early RNA sequences are within the bounds of synthetic credibility.

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Fig. 1: Summary of previous and present work.
Fig. 2: 5′ phosphorylation of 2-thiouridine 8 in concentrated formamide solution.
Fig. 3: Prebiotic and synthetic routes to (thio)anhydronucleosides.
Fig. 4: Phosphorylation of thionucleosides under mild conditions with DAP.
Fig. 5: Photoinduced reduction of thioanhydrouridine with hydrosulfide (HS) and its proposed mechanism.
Fig. 6: Hydrolysis and transglycosylation reactions of 2′-deoxy-2-thiouridine 11.

Data availability

Full experimental details and data are provided in the Supplementary Information. The raw data for Supplementary Figs. 4953 are available from the authors upon reasonable request. Correspondence and requests for materials should be addressed to J.D.S. and R.K.

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Acknowledgements

This work was supported by the Medical Research Council (number MC_UP_A024_1009) and grants from the Simons Foundation (number 290362 to J.D.S. and number 327124 to R.K.). We acknowledge P. B. Rimmer for discussions on the photochemical reactor setup.

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J.D.S. and R.K. supervised the experimental research. J.X., N.J.G. and C.G. performed the experiments. All of the authors co-wrote the paper and assembled the Supplementary Information.

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Correspondence to Ramanarayanan Krishnamurthy or John D. Sutherland.

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All experimental procedures, characterization data (NMR, MS, UV and HPLC) for compounds and additional data referenced in the manuscript.

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Xu, J., Green, N.J., Gibard, C. et al. Prebiotic phosphorylation of 2-thiouridine provides either nucleotides or DNA building blocks via photoreduction. Nat. Chem. 11, 457–462 (2019). https://doi.org/10.1038/s41557-019-0225-x

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