Prebiotic selection and assembly of proteinogenic amino acids and natural nucleotides from complex mixtures

Abstract

UK 2A central problem for prebiotic synthesis of the biological amino acids and nucleotides is avoiding the concomitant synthesis of undesired or irrelevant byproducts. Additionally, multistep pathways require mechanisms that enable the sequential addition of reactants and purification of intermediates that are consistent with reasonable geochemical scenarios. Here, we show that 2-aminothiazole reacts selectively with two-and three-carbon sugars (glycolaldehyde and glyceraldehyde, respectively), which results in their accumulation and purification as stable crystalline aminals. This permits ribonucleotide synthesis, even from complex sugar mixtures. Remarkably, aminal formation also overcomes the thermodynamically favoured isomerisation of glyceraldehyde to dihydroxyacetone because only the aminal of glyceraldehyde separates from the equilibrating mixture. Finally, we show that aminal formation provides a novel pathway to amino acids that avoids synthesis of the non-proteinogenic α,α-disubstituted analogues. The common physicochemical mechanism that controls proteinogenic amino acid and ribonucleotide assembly from prebiotic mixtures suggests these essential classes of metabolite had a unified chemical origin. 3The conservation of the genetic code, amino acids, and nucleotides in biology suggests a single origin of life on Earth. [1][2][3][4][5][6][7][8][9][10][11][12][13] Proteins are built from a highly restricted set of about 20 amino acids according to a universal triplet code of four ribonucleotides. Therefore, it is essential to learn how this specific small constellation of molecules became irrevocably linked at the advent of life. In contrast to the narrow distribution of universal metabolites observed in biology, typical prebiotic reactions are notorious for their complex product distributions. Accordingly, it has been recognised that "the chief obstacle to understanding the origin of RNA-based life is identifying a plausible mechanism for overcoming the clutter wrought by prebiotic chemistry". [4][5][6][7] For example, the most-efficient and specific proposed prebiotic pathway to the pyrimidine ribonucleotides requires synthesis of the key intermediate pentose aminooxazoline (1) (Fig. 1a). [2][3][4][5][6][22][23][24] However, the plausibility of this proposed prebiotic synthesis of pentose aminooxazoline (1) has been questioned because it is contingent upon the strictly controlled sequential delivery of pure glycolaldehyde (2a) to cyanamide (3) to yield 2-aminooxazole (4), followed by pure glyceraldehyde (2b) to 2-aminooxazole (4) to yield the desired product (Fig. 1a). This is a serious problem because both of these reactions lack the intrinsic selectivity required to exclusively yield their respective products (2-aminooxazole (4) and pentose aminooxazoline (1)) from mixtures of glycolaldehyde (2a) and glyceraldehyde (2b). The problem becomes increasingly worse in the presence of other sugars. Without a separate and sequential delivery of glycolaldehyde (2a) and glyceraldehyde (2b), a complex mixture...

Prebiotic Systems Chemistry: Complexity Overcoming Clutter

“…61 The formation and persistence of glyceraldehyde 20 is highly significant because, as previously mentioned, the corresponding cyanohydrin of glyceraldehyde 20 can undergo selfdestruction by rapid imidolactone formation at elevated pH. 35,36 However, the cyanohydrin of glyceraldehyde 20 is stable under the mild (pH 7, phosphate buffered) reaction conditions employed in Sutherland's Kilani-Fischer homologation. 60 Glyceraldehyde 20 synthesis by cyanide capture and photochemical reduction bears interesting similarities to the strategy used in the Calvin cycle, where enzyme-catalyzed CO 2 capture and reduction produces glyceraldehyde-3-phosphate 20-3P.…”

“…To demonstrate the consequences of this, the amount of pentose aminooxazoline 31 formation is so little when pre-equilibrated mixtures of glycolaldehyde 14 and triose sugars 20 and 22 are exposed to 2-aminoxazole 32 that even the privileged crystallinity of ribo-31 can no longer resolve this mixture. 36 So while the reaction of glyceraldehyde 20 and 2-aminooxazole 32 is exceedingly clean, the prospects of this reaction furnishing sufficiently pure ribonucleotide precursors is thwarted by an increasing amount of 'prebiotic clutter'. Specifically, there is no resolution between the reactivity of C 2 and C 3 sugars.…”

“…Rapid imidolactone formation occurs by the intramolecular (5-exo-dig) hydroxyl addition to the nitrile carbon atom of the cyanohydrin that forms from the parent sugar, and this leads to its eventual hydrolysis to homologous acids rather than sugars. 35,36 The ramifications of this are the (apparent) need for segregation of nucleobases and sugars syntheses. Then, assuming this separation is geochemically possible, exclusive nitrogenous (cyanide 9) or oxygenous (formaldehyde 12) oligomerization does not allow effective formation of nucleobases or pentose sugars with the selectivity or the robustness to be considered as viable processes to yield either ribose 7 or nucleobases 3-6 (or any other non-biological nucleobase analogue) required for nucleotide assembly.…”

“…However, a solution to all of these problems has recently been found by way of 2-aminothiazole 44 mediated physicochemical processes that result in the high yielding and chemoselective formation of pentose aminooxazolines 31 from remarkably complex mixtures. 36 This is achieved by selective sequestration of glycolaldehyde 14 and glyceraldehyde 20 from highly complex sugar mixtures ( Figure 9). …”

The Origin of Life on Earth and the Design of Alternative Life Forms

“…Even more amazingly, there is another very similar molecule, 2-aminothiazole (2AT), in which the oxygen of 2AO is replaced with sulfur. This compound can react with and store, in a stable crystalline form, the simple 2 and 3 carbon sugars that are needed to make nucleotides and amino acids 23 . I fi nd it amazing that these three very closely related molecules, all made by simple chemistry from simple starting materials in the same or very similar environments, can go on to play different roles in building RNA molecules -this seems like a strong clue that this chemistry is truly relevant to the prebiotic chemistry of the early earth.…”