Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions

Abstract

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' hypothesis this polymer was RNA, but attempts to provide experimental support for this have failed. In particular, although there has been some success demonstrating that 'activated' ribonucleotides can polymerize to form RNA, it is far from obvious how such ribonucleotides could have formed from their constituent parts (ribose and nucleobases). Ribose is difficult to form selectively, and the addition of nucleobases to ribose is inefficient in the case of purines and does not occur at all in the case of the canonical pyrimidines. 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 molecules, 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.

Formamide and the origin of life

“…Then, we comment on the fact that the origin of nucleosides is the weakest link in this possible chain of events. Recent findings suggest a solution [28], for conditions probably different from those that supposedly characterized prebiotic processes (namely: simplicity, robustness and availability of abundant precursors). Formamide chemistry allows the formation of acyclonucleosides in non-demanding conditions [29].…”

“…On the basis of existing data, the direct condensation of sugar and natural nucleic bases does not work efficiently under prebiotic conditions either for kinetic and thermodynamic reasons [97]. Examples of the two other reaction pathways of possible prebiotic interest have been reported: 1) β-ribocytidine-2 ,3 -cyclic phosphate was synthesized with high stereoselectivity by a multistep process starting from glycoladehyde and cyanamide through a pentose amino-oxazoline derivative on which the cytosine scaffold was gradually built [28]. The use of amino pentose-oxazolines as intermediates in the synthesis of nucleoside derivatives is a well-known practice in medicinal chemistry [98].…”

“…The correlation between the [27] and to the closed-ring phosphorylation of nucleosides [30]. The abiotic synthesis of nucleosides was reported [28,158]. The spontaneous generation of RNA oligomers from purine 3 ,5 -cyclic nucleotides [31] and their non-enzymatic ligation in water [129,130] were described.…”

Complex Chemical Reaction Networks from Heuristics-Aided Quantum Chemistry

“…of hydrogen cyanide and formamide to nitrogen heterocycles; 67 the triose-ammonia reaction; 68,69 and the nucleoside synthesis recently suggested by Sutherland and co-workers. 70,71 Detailed studies of these and other abiotic reaction networks may help to elucidate common properties of reaction networks and differences from networks formed by evolution. Work along these lines is described in our companion publication.…”

Prebiotic chemical kinetics imprint on positional codon usage

“…12 On the other hand, the selective formation of ribose is rather a difficult process, and remained a matter of debate, even though a number of studies have shown that activated ribonucleotides polymerize to form RNA. Recently, this missing link has been addressed by the work of Powner et al 18 Their experiments have shown that activated pyrimidines ribonucleotides can be formed, bypassing free ribose and the nucleobases, starting from cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphate, all plausible prebiotic feedstock molecules, and synthesis conditions that are consistent with early-Earth geochemical models.…”