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.2017 May 19:8:15270.
doi: 10.1038/ncomms15270.

Divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides

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Divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides

Shaun Stairs et al. Nat Commun..

Abstract

Understanding prebiotic nucleotide synthesis is a long standing challenge thought to be essential to elucidating the origins of life on Earth. Recently, remarkable progress has been made, but to date all proposed syntheses account separately for the pyrimidine and purine ribonucleotides; no divergent synthesis from common precursors has been proposed. Moreover, the prebiotic syntheses of pyrimidine and purine nucleotides that have been demonstrated operate under mutually incompatible conditions. Here, we tackle this mutual incompatibility by recognizing that the 8-oxo-purines share an underlying generational parity with the pyrimidine nucleotides. We present a divergent synthesis of pyrimidine and 8-oxo-purine nucleotides starting from a common prebiotic precursor that yields the β-ribo-stereochemistry found in the sugar phosphate backbone of biological nucleic acids. The generational relationship between pyrimidine and 8-oxo-purine nucleotides suggests that 8-oxo-purine ribonucleotides may have played a key role in primordial nucleic acids prior to the emergence of the canonical nucleotides of biology.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Proposed prebiotic ribonucleotide synthesis by divergent nucleobase assembly on a universal furanosyl-oxazoline scaffold.
(a) Unitary phase: the reaction of prebiotically available feedstock molecules to assemble a universal sugar scaffold. (b) Divergent phase: single sugar scaffold diverges through congruent reactions to yield both pyrimidine and purine precursors with controlled furanosyl sugar structure, pentose selectivity and stereocontrol. R′=CN or CONH2. (c) Convergent phase: concomitantly synthesized purine and pyrimidine nucleotides are collectively assembled to yield polymeric RNAs.
Figure 2
Figure 2. Divergent ribonucleotide synthesis.
Prebiotic assembly of cytidine-2′,3′-cyclic phosphate3C, uridine-2′,3′-cyclic phosphate3U, 8-oxo-adenosine-2′,3′-cyclic phosphate3OA and 8-oxo-inosine-2′,3′-cyclic phosphate3OI. Glycolaldehyde (5) reacts with cyanamide (6) and thiocyanic acid (9) to furnish 2-aminooxazole4a and 2-thiooxazole4b, respectively. 2-Aminooxazole4a is a known prebiotic precursor of pyrimidine nucleotides (3C and3U) and 2-thiooxazole4b is demonstrated to be a precursor of both pyrimidine nucleotides (3C and3U) and 8-oxo-purine nucleotides (3OA and3OI). Oxazole4b undergoes reaction with glyceraldehyde (7) to yield thione1a. Chemical activation of thione1a provides a second point of divergence (thione1b), which yields pyrimidine precursor10a upon reaction with ammonia (2a) or purine precursors16b or16c upon reaction with hydrogen cyanide oligomers (2b or2c, respectively). Cyanovinylation and formylation of10a and16b/c and subsequent urea-mediated phosphorylation leads to the congruent synthesis of pyrimidine nucleotides (3C and3U) and 8-oxo-purine nucleotides (3OA and3OI). The two points of chemical divergence, Divergence A and divergence B, are marked with green boxes and the chemical convergence, Convergence, on nucleotide monomers is marked with an orange box.
Figure 3
Figure 3. Model quinazolinedione synthesis.
One-pot cyanovinylation of arabinofuranosyl-oxazolidinone thione (1a) and quinazolinedione12a synthesis in water was tested as a model nucleobase synthesis strategy to investigate the pH dependence of cyanovinyl- and alkyl-sulfide displacement fromS-cyanovinyl arabinofuranosyl-oxazolidinone thione (1b) andS-methyl arabinofuranosyl-oxazolidinone thione (1c), respectively. Single crystal X-ray structure of ribo-quinazolinedione (ribo-12a) and arabino-quinazolinedione (arabino-12a).
Figure 4
Figure 4. Divergent aminooxazoline synthesis by sulfide displacement.
(a) Ammonia (2a) displacement of cyanovinylthiolate13 from cyanovinyl arabinofuranosyl-oxazolidinone thione (1b) to furnish pyrimidine precursor arabinofuranosyl-aminooxazoline (10a) and concomitantly regenerate arabinofuranosyl-oxazolidinone thione (1a). (b) Aminonitrile2b–d displacement to furnish purine precursors arabinofuranosyl-aminooxazoline10b–d, and selective cyclization of arabinofuranosyl-aminooxazoline10b–c to aminoimidazoles16b and16c. (c) Single crystal X-ray structure of dicyanovinyl sulfide (15), arabinofuranosyl-oxazolidinone thione (1a), cyanovinyl arabinofuranosyl-oxazolidinone thione (1b), arabinofuranosyl-aminoimidazole (16b) and arabinofuranosyl-aminoimidazole (16c).
Figure 5
Figure 5. Aminoimidazole formylation.
Incubation of aminoimidazole (16b–c) in formamidine/formamide solution yields anhydropurines17A and17I, respectively. Formamidine and hydrogen cyanide in formamide provide comparable yields for formylation of16c, whereas formamidine provides an excellent yield of17A from16b likely exploiting the electrophilicity of the nitrile moiety of16b.
Figure 6
Figure 6. Urea-mediated phosphorylation of 8,2′-O-cyclo-purines.
(a) Urea-mediated phosphorylation of 8,2′-O-cyclo-adenine (17A) and 8,2′-O-cyclo-inosine (17I) to yield 8-oxo-adenosine-2′,3′-cyclic phosphate (3OA) and 8-oxo-inosine-2′,3′-cyclic phosphate (3OI). (b) Equilibration of 8,2′-O-cyclo-adenine (17A) with 8,5′-anhydro-8-oxyadenine (19) and 2′,3′-anhydro-8-oxo-adenosine (20) upon incubation in alkaline solution. (c) Urea-mediated conversion of bisphosphate18 to monophosphate3, driven by the irreversible synthesis of 2′,3′-cyclic phosphates. (d) Single crystal X-ray structures of anhydrocytidine (11), 8,2′-O-cyclo-adenine (17A), 8,2′-O-cyclo-inosine (17I), 8,5′-anhydro-8-oxyadenine (19) and 2′,3′-anhydro-8-oxo-adenosine (20). Structure11 was reported in ref. and is shown for comparison to structures17A and17I.
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