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.
Highlights
The metabolic network is a large cellular system that generates life’s building blocks including amino acids, nucleotides, and lipids
The potential formation of F16BP was monitored for 14 d, which is much longer as the stability of glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) would have permitted their condensation to occur (Fig. S1A)
Glycolysis and the pentose phosphate pathway, which exist in several variants, are evolutionarily ancient and their intermediates are of key importance for some of the most crucial processes that define life
Summary
The metabolic network is a large cellular system that generates life’s building blocks including amino acids, nucleotides, and lipids. Gluconeogenesis rebuilds the C-C bonds cleaved in glycolysis in one particular reaction, the aldol addition of D-glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) forming the much more stable fructose 1,6-bisphosphate (F16BP) It is still unknown how an early metabolism produced the sugar phosphates central for life. The coupling of the aldolase to the subsequent phosphatase reaction in the ancient Archaean enzyme paralogue renders gluconeogenesis unidirectional, leading to the formation of the large sugar phosphates in parallel to the occurrence of glycolysis in the same organism. This enzyme has been named the “pacemaker” for gluconeogenesis.
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