AU The:structure Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly of the metabolic network is highly conserved, but : we know little about its evolutionary origins. Key for explaining the early evolution of metabolism is solving a chicken–egg dilemma, which describes that enzymes are made from the very same molecules they produce. The recent discovery of several nonenzymatic reaction sequences that topologically resemble central metabolism has provided experimental support for a “metabolism first” theory, in which at least part of the extant metabolic network emerged on the basis of nonenzymatic reactions. But how could evolution kick-start on the basis of a metal catalyzed reaction sequence, and how could the structure of nonenzymatic reaction sequences be imprinted on the metabolic network to remain conserved for billions of years? We performed an in vitro screening where we add the simplest components of metabolic enzymes, proteinogenic amino acids, to a nonenzymatic, iron-driven reaction network that resembles glycolysis and the pentose phosphate pathway (PPP). We observe that the presence of the amino acids enhanced several of the nonenzymatic reactions. Particular attention was triggered by a reaction that resembles a rate-limiting step in the oxidative PPP. A prebiotically available, proteinogenic amino acid cysteine accelerated the formation of RNA nucleoside precursor ribose-5-phosphate from 6-phosphogluconate. We report that iron and cysteine interact and have additive effects on the reaction rate so that ribose-5-phosphate forms at high specificity under mild, metabolism typical temperature and environmental conditions. We speculate that accelerating effects of amino acids on rate-limiting nonenzymatic reactions could have facilitated a stepwise enzymatization of nonenzymatic reaction sequences, imprinting their structure on the evolving metabolic network.
We thank Markus Keller and members of the Ralser group for valuable discussions and critical comments, Olivier Languin-Cattoen and Maria Ouvarova for help in the nonenzymatic reaction screening, and Dr. Jae-Hun Jeoung (Humboldt University Berlin) for assistance in carrying out anaerobic reactions.
This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), and the Wellcome Trust (FC001134). MR received support from the Wellcome Trust (200829/Z/16/Z) and the Ministry of Education and Research (BMBF), as part of the National Research Node ‘Mass spectrometry in Systems Medicine (MSCoresys), under grant agreement 031L0220A. JLG was supported by the Medical Research Council UK (MR/P011705/1, MC_UP_A090_1006). GP acknowledges support by a Talento program fellowship from Comunidad de Madrid. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.