Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice

Abstract

The evolutionary origins of metabolism, in particular the emergence of the sugar phosphates that constitute glycolysis, the pentose phosphate pathway, and the RNA and DNA backbone, are largely unknown. In cells, a major source of glucose and the large sugar phosphates is gluconeogenesis. This ancient anabolic pathway (re-)builds carbon bonds as cleaved in glycolysis in an aldol condensation of the unstable catabolites glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, forming the much more stable fructose 1,6-bisphosphate. We here report the discovery of a nonenzymatic counterpart to this reaction. The in-ice nonenzymatic aldol addition leads to the continuous accumulation of fructose 1,6-bisphosphate in a permanently frozen solution as followed over months. Moreover, the in-ice reaction is accelerated by simple amino acids, in particular glycine and lysine. Revealing that gluconeogenesis may be of nonenzymatic origin, our results shed light on how glucose anabolism could have emerged in early life forms. Furthermore, the amino acid acceleration of a key cellular anabolic reaction may indicate a link between prebiotic chemistry and the nature of the first metabolic enzymes.T he metabolic network is a large cellular system that generates life's building blocks including amino acids, nucleotides, and lipids. Most of the metabolic pathways that participate in this network are well understood, but their evolutionary origin remains an unsolved problem. The network contains many reactive and unstable intermediates, yet its topological organization is widely conserved and considered ancient. It has therefore been extensively debated to what extent this structure could be the result of Darwinian selection and thus be of postgenetic origin or whether the metabolic network topology dates back to a nonenzymatic chemistry (1-4). A series of recently discovered chemical networks provide evidence for the latter. In the presence of simple inorganic ions as found in Archean sediment, and under conditions that are reminiscent of the chemistry that operates in cells, nonenzymatic reactions replicate essential topological elements of the most central metabolic pathways. Nonenzymatic chemical reactions currently replicate glycolysis (including the EmbdenMeyerhof-Parnas pathway, the Entner-Doudoroff pathway, and their many variants), the pentose phosphate pathway, the catabolic reactions of the TCA cycle, and the formation of the methyl group donor S-adenosylmethionine (5-8). Moreover, reactions of glycolysis and the pentose phosphate pathway, as well as reactions replicating the oxidative TCA cycle, can each occur in distinct but unifying reaction milieus, respectively. This implies that simple inorganic catalysts were shaping the topological structure of the metabolic network. In other words, the reactions that sugar phosphates undergo in the presence of the highest concentrated transition metal in Archean sediment [Fe(II)] and the reactions that TCA intermediates undergo in the presence of sulfate radicals are reflected i...

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