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Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions


At some stage in the origin of life, an informational polymer must have arisen by purely chemical means. According to one version of the ‘RNA world’ hypothesis1,2,3 this polymer was RNA, but attempts to provide experimental support for this have failed4,5. In particular, although there has been some success demonstrating that ‘activated’ ribonucleotides can polymerize to form RNA6,7, it is far from obvious how such ribonucleotides could have formed from their constituent parts (ribose and nucleobases). Ribose is difficult to form selectively8,9, and the addition of nucleobases to ribose is inefficient in the case of purines10 and does not occur at all in the case of the canonical pyrimidines11. Here we show that activated pyrimidine ribonucleotides can be formed in a short sequence that bypasses free ribose and the nucleobases, and instead proceeds through arabinose amino-oxazoline and anhydronucleoside intermediates. The starting materials for the synthesis—cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphate—are plausible prebiotic feedstock molecules12,13,14,15, and the conditions of the synthesis are consistent with potential early-Earth geochemical models. Although inorganic phosphate is only incorporated into the nucleotides at a late stage of the sequence, its presence from the start is essential as it controls three reactions in the earlier stages by acting as a general acid/base catalyst, a nucleophilic catalyst, a pH buffer and a chemical buffer. For prebiotic reaction sequences, our results highlight the importance of working with mixed chemical systems in which reactants for a particular reaction step can also control other steps.

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Figure 1: Pyrimidine ribonucleotide assembly options.
Figure 2: Development of the synthesis of 2-amino-oxazole 11.
Figure 3: Pentose amino-oxazoline stability, and assembly chemistry.
Figure 4: Formation and phosphorylation of the arabinose anhydronucleoside 13.
Figure 5: Photochemistry of β-ribocytidine-2′,3′-cyclic phosphate 1.

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This work has been funded by the UK Engineering and Physical Sciences Research Council through the provision of a postdoctoral fellowship (B.G.) and a PhD studentship (M.W.P.). We thank J. Raftery and M. Helliwell for X-ray crystallography.

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Correspondence to John D. Sutherland.

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X-ray crystallographic data (excluding structure factors) for 13 have been deposited at the Cambridge Crystallographic Data Centre, UK, under deposition number CCDC 701055. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre (

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This file contains Supplementary Methods and Data with Supplementary Figures S1-S13 and Supplementary References. (PDF 2705 kb)

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Powner, M., Gerland, B. & Sutherland, J. Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. Nature 459, 239–242 (2009).

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