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Divergent Prebiotic Synthesis of Pyrimidine and 8-Oxo-Purine Ribonucleotides

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Divergent Prebiotic Synthesis of Pyrimidine and 8-Oxo-Purine Ribonucleotides ARTICLE Received 20 Dec 2016 | Accepted 15 Mar 2017 | Published 19 May 2017 DOI: 10.1038/ncomms15270 OPEN Divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides Shaun Stairs1,*, Arif Nikmal1,*, Dejan-Kresˇimir Bucˇar1, Shao-Liang Zheng2, Jack W. Szostak2,3 & Matthew W. Powner1 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 b-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. 1 Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK. 2 Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA. 3 Department of Molecular Biology and Center for Computational and Integrative Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to M.W.P. (email: [email protected]). NATURE COMMUNICATIONS | 8:15270 | DOI: 10.1038/ncomms15270 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15270 ibonucleotide synthesis is a key unmet requirement upon which the origin of life on Earth is contingent1–3. Recent a HO progress towards prebiotic ribonucleotide synthesis O R Prebiotic NH uniformly fails to account for simultaneous access to both feedstocks 4–6 7–11 S pyrimidine and purine nucleotides, both of which are HO O required to generate RNA. Despite purine nucleobase synthesis by 1a hydrogen cyanide oligomerization being first reported more than 60 years ago3,9–11, purine nucleobases and adenosine nucleotides are only accessible in low yields and with poor regio- and b stereoselectivity7,11. While, a prebiotically plausible synthesis of NH both pyrimidine ribonucleotides has been established4–6, the HO HO 2 O O R′ glycosidations of adenine and hypoxanthine generate a complex N N mixture of nucleoside-like products, and there is no literature N O NH2 precedent for the direct glycosidation of guanine to furnish HO HO O 3,11 guanosine (G) . A notable proposed pathway to the purine 10a 16 nucleotides, that achieves excellent N9-selectivity during ribosylation7, remains problematic because of an unselective ribosylation (that furnished a mixture of natural furanosyl and non-natural pyranosyl isomers, and a mixture of natural b-anomers and non-natural a-anomers). Furthermore, this Pyrimidines Purines strategy, a variant of the classic Traube purine synthesis8, generates a wide spectrum of glycone isomers, homologues and anomers alongside a low yield of natural nucleosides from c prebiotically plausible sugar mixtures7. Therefore, in an inversion to the status quo of more than 50 years, a selective prebiotically RNA plausible purine synthesis is now the most significant problem associated with prebiotic assembly of the RNA monomers. Remarkably, all proposed prebiotic syntheses of pyrimidine Figure 1 | Proposed prebiotic ribonucleotide synthesis by divergent and purine nucleotides have yielded either pyrimidines or purines 4–7,9–12 nucleobase assembly on a universal furanosyl-oxazoline scaffold. separately, but never (yet) both by the same strategy ; while (a) Unitary phase: the reaction of prebiotically available feedstock purine nucleotides can be synthesized by direct ribosylation, molecules to assemble a universal sugar scaffold. (b) Divergent phase: pyrimidine nucleotides cannot and though a complete stepwise single sugar scaffold diverges through congruent reactions to yield both pyrimidine nucleotide synthesis has been demonstrated 5 pyrimidine and purine precursors with controlled furanosyl sugar structure, (even from complex sugar mixtures ) a comparable strategy for 0 4–6 pentose selectivity and stereocontrol. R ¼ CN or CONH2. (c) Convergent purine synthesis remains elusive . Constitutional analysis of phase: concomitantly synthesized purine and pyrimidine nucleotides are purine and pyrimidine ribonucleotides suggests that nucleobase collectively assembled to yield polymeric RNAs. construction on a preformed sugar moiety would provide the simplest strategy for divergent monomer synthesis (Fig. 1). Given the lack of specificity observed during direct glycosidation of purine nucleobases, we have previously suggested that a tethered Results purine synthesis would overcome the limitation of intramolecular Overview. We envisaged that a purine-8,20-anhydronucleoside glycosidation13,14. Although the optimal tethering-site to direct linkage could be exploited to deliver regio- and stereospecific stereo- and regiospecific purination is not clear; it is of particular glycosidation, with direct generational parity to prebiotic note that the canonical purine nucleotides, unlike the pyrimidine pyrimidine synthesis via a pyrimidine-2,20-anhydronucleoside nucleotides, display significant variation in their oxidation level. intermediate (Fig. 2)4. We hypothesized that positioning sulfur at Nucleosides A and G are both universal and essential to biology, the C2-carbon atom of an oxazolidinone thione (1), followed by but interestingly they have different oxidation levels. We there- chemoselective sulfide-activation and amine displacement, fore hypothesized that the inherent flexibility in purine oxidation would provide the chemical differentiation required for level may shed light upon the ideal prebiotic tether to allow divergent pyrimidine (amine ¼ ammonia, 2a) and 8-oxo-purine divergent purine and pyrimidine synthesis. Purines particularly (amine ¼ HCN-trimer, 2b–c) nucleotide synthesis from one have a high propensity for C8-oxidation and 8-oxo-guanine common precursor. A common thione precursor would (OG), for example, which though commonly mutagenic because bypass the unstable free sugars and problematic direct purine it may give rise to G:C to T:A transversions via DNA Hoogsteen nucleobase glycosidation, and move us a step closer to OG:A base pairs, is remarkably well tolerated during information understanding the unified origins of purine and pyrimidine transfer in Watson–Crick OG:C base pairs15–21. Moreover, nucleotides in biology. E. coli DNA polymerase I and Taq DNA polymerase have both been observed to exclusively insert a correct thymine (T) nucleotide when reading through 8-oxo-adenine (OA) Furanosyl-selective sugar synthesis. Oxazole 4a is a key incorporated into gene fragments22. Importantly, with respect ribonucleotide precursor which derives from glycolaldehyde (5) to analysis of selective purine nucleotide assembly, C8-oxidation and cyanamide (6) (Fig. 2)4. The C2-carbon atom of 4a is appears to provide an ideally positioned tether for prebiotic regiospecifically positioned as the C2-pyrimidine carbon atom in purine nucleobase assembly by an approach that is unified with abiotic pyrimidine synthesis upon reaction with glyceraldehyde prebiotic pyrimidine synthesis. Here, we demonstrate a divergent, (7) and cyanoacetylene (8). To introduce a sulfur atom at the prebiotically plausible reaction strategy for the synthesis of C2-carbon atom of oxazole 4b, and consequently acquire the both pyrimidine and purine ribonucleotides (3) on a single plasticity needed to diverge towards both purine and pyrimidine oxazoline scaffold. nucleotides, we reasoned that synthesis should commence with 2 NATURE COMMUNICATIONS | 8:15270 | DOI: 10.1038/ncomms15270 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15270 ARTICLE Divergence A H2N CN O HS CN 6 9 NH O NH2 N CN O S O NH2 OH H2N CN H2N CN 5 4b 4a 2b 2c O OH O OH OH OH 7 7 Divergence B NH HO HO HO 2 NH3 H NR′ O O O 2 R″ N 2a N 2b-c N N R=CHCHCN R=CHCHCN or Me NH2 SR O HO O HO O HO 16b R″=CN 10a 1a R=H 8 16c R″=CONH 1b R=CHCHCN 2 MeSH 1c R=Me CN HC(NH)NH2 8 HCONH2 Convergence HO N HO HO OH HO OH HO N O O P B P O N N O O O O Y NH2 N N CO(NH ) CO(NH ) O HO O 2 2 O O 2 2 HO P HCONH2 HCONH2 11 O O 17A Y=NH2 17I Y=OH 3C B=cytosine 3U B=uracil 3OAB=8-oxo-adenine 3OI B=8-oxo-hypoxanthine Figure 2 | Divergent ribonucleotide synthesis. Prebiotic assembly of cytidine-20,30-cyclic phosphate 3C, uridine-20,30-cyclic phosphate 3U, 8-oxo- adenosine-20,30-cyclic phosphate 3OA and 8-oxo-inosine-20,30-cyclic phosphate 3OI. Glycolaldehyde (5) reacts with cyanamide (6) and thiocyanic acid (9) to furnish 2-aminooxazole 4a and 2-thiooxazole 4b, respectively. 2-Aminooxazole 4a is a known prebiotic precursor of pyrimidine nucleotides (3C and 3U) and 2-thiooxazole 4b is demonstrated to be a precursor of both pyrimidine nucleotides (3C and 3U) and 8-oxo-purine nucleotides
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