The RNA world and the origin of metabolic enzymes

Abstract

An RNA world has been placed centre stage for explaining the origin of life. Indeed, RNA is the most plausible molecule able to form both a (self)-replicator and to inherit information, necessities for initiating genetics. However, in parallel with self-replication, the proto-organism had to obtain the ability to catalyse supply of its chemical constituents, including the ribonucleotide metabolites required to replicate RNA. Although the possibility of an RNA-catalysed metabolic network has been considered, it is to be questioned whether RNA molecules, at least on their own, possess the required catalytic capacities. An alternative scenario for the origin of metabolism involves chemical reactions that are based on environmental catalysts. Recently, we described a non-enzymatic glycolysis and pentose phosphate pathway-like reactions catalysed by metal ions [mainly Fe(II)] and phosphate, simple inorganic molecules abundantly found in Archaean sediments. While the RNA world can serve to explain the origin of genetics, the origin of the metabolic network might thus date back to constraints of environmental chemistry. Interestingly, considering a metal-catalysed origin of metabolism gives rise to an attractive hypothesis about how the first enzymes could have formed: simple RNA or (poly)peptide molecules could have bound the metal ions, and thus increased their solubility, concentration and accessibility. In a second step, this would have allowed substrate specificity to evolve.

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

“…Indeed, the origin of complex multistep metabolic pathways is difficult to explain solely by Darwinian selection in the absence of a chemical template. This implies that metabolic pathways date back topologically to chemical networks (36,37). A key aspect of the nonenzymatic formation of fructose 1,6-bisphosphate is the acceleration of the reaction by simple amino acids, in particular glycine, the formation of which has been repeatedly reported even in the earliest attempts of simulating prebiotic processes, as in the Miller-Urey experiment (38).…”

Single amino acid-promoted reactions link a non-enzymatic chemical network to the early evolution of enzymatic pentose phosphate pathway

“…In turn, the "end-product"-forming enzyme can only be selected for after the intermediates are in place. Non-enzymatic, chemical networks might be the basis to overcome this conundrum, by providing an underlying web of subtle preset transformations, upon which Darwinian selection can operate (5). If this hypothesis were true, metabolic pathways that catalyzed a similar set of reactions could come into being multiple times and independently to one another.…”

“…The evolutionary origins of enzymatic metabolism are subject to a long-lasting debate (1)(2)(3)(4)(5)(6) but remain essentially unknown. The history of Biochemistry and the evolution of biochemical thinking have fundamentally shaped this debate.…”

“…In this manuscript, we aim to address a question that emerges from these observations: How could a metal-ion driven, chemical network prime a Darwinian process that eventually forms an enzyme-catalyzed metabolic pathway? Indeed, as early as in 1945, Horowitz described a main difficulty to explain the advent of enzymatic catalysis by Darwinian evolution, as a chicken-egg dilemma, that we have previously referred to as the 'End Product Problem' (5,38): Darwinian pressure can only select for a functional product, the 'end product' of an enzymatic pathway. But how could then evolve the enzyme that catalyzes the formation of an upstream intermediate, one that is needed before formation of the functional product is conceived?…”

“…We speculate that the presence of a non-enzymatic chemical network could overcome the end product problem (5). If a reaction network is already present due to non-enzymatic interconversion of metabolites, Darwinian selection can then improve the end product formation by selecting an enzyme that enhances its most rate-limiting reaction.…”