Harnessing chemical energy for the activation and joining of prebiotic building blocks

Abstract

Life is an out-of-equilibrium system sustained by a continuous supply of energy. In extant biology, the generation of the primary energy currency, adenosine 5'-triphosphate and its use in the synthesis of biomolecules require enzymes. Before their emergence, alternative energy sources, perhaps assisted by simple catalysts, must have mediated the activation of carboxylates and phosphates for condensation reactions. Here, we show that the chemical energy inherent to isonitriles can be harnessed to activate nucleoside phosphates and carboxylic acids through catalysis by acid and 4,5-dicyanoimidazole under mild aqueous conditions. Simultaneous activation of carboxylates and phosphates provides multiple pathways for the generation of reactive intermediates, including mixed carboxylic acid-phosphoric acid anhydrides, for the synthesis of peptidyl-RNAs, peptides, RNA oligomers and primordial phospholipids. Our results indicate that unified prebiotic activation chemistry could have enabled the joining of building blocks in aqueous solution from a common pool and enabled the progression of a system towards higher complexity, foreshadowing today's encapsulated peptide-nucleic acid system.

Fig. 1. Joining of prebiotic building blocks driven by common activation chemistry in aqueous solution.

a) Model reaction of A3'P and carboxylates upon activation. The mixed anhydride intermediate 6 can give either 4 or 5. b) Model reaction of A5'P and carboxylates upon activation. The mixed anhydride 10 is reminiscent of structurally analogous intermediates common to peptide and phospholipid biosynthesis. c) Formation of peptides upon activation. d) Simultaneous activation of carboxylates and phosphates under unified activation conditions. Carboxylates (aliphatic, peptidic and amino acids) are highlighted in blue, the catalyst, DCI 7, is shown in orange and the activating reagent, methyl isonitrile 1, is shown in green. Ade: Adenine.

Fig. 2. Proposed reaction scheme of the activation chemistry.

From top to bottom, four distinct chemical stages are highlighted in different colors. The first stage encompasses the prebiotic synthesis of building blocks, activating reagents, catalysts and other species. The second stage is activating reagent dependent, and the activating reagent is covalently attached to carboxylates or phosphates in the form of intermediates 11, 12 and 13. A dashed boxed includes two potential alternative pathways by which the activation chemistry mediated by methyl isonitrile 1 may be initiated. The third stage is activating reagent independent and is characterized by common intermediates such as 6, 8, 10 and 14. The formation of these intermediates could in principle be driven by alternative activating reagents. The fourth stage involves the condensation of various species to form oligopeptides, peptidyl-RNAs, RNAs and primordial phospholipids. Pathways involving catalysis by DCI 7 are highlighted in orange, and bold arrows indicate steps preferentially taken. Carboxyl moieties including aliphatic carboxylic acids, N-acyl amino acids and peptides, are highlighted in blue. All the activated carboxylates and phosphates are prone to hydrolysis but these reactions are omitted for the sake of clarity.