Abstract
The universality of many pathways of core metabolism suggests a strong role for evolutionary selection, but it remains unclear whether existing pathways have been selected from a large or small set of biochemical possibilities. To address this question, we construct in silico all possible biochemically feasible alternatives to the trunk pathway of glycolysis and gluconeogenesis, one of the most highly conserved pathways in metabolism. We show that, even though a large number of alternative pathways exist, the alternatives carry lower flux than the real pathway under typical physiological conditions. We also find that if physiological conditions were different, different pathways could outperform those found in nature. Together, our results demonstrate how thermodynamic and biophysical constraints restrict the biochemical alternatives that are open to evolution, and suggest that the existing trunk pathway of glycolysis and gluconeogenesis may represent a maximal flux solution.
Highlights
The universality of many pathways of core metabolism suggests a strong role for evolutionary selection, but it remains unclear whether existing pathways have been selected from a large or small set of biochemical possibilities
Central carbon metabolism consists exclusively of reactions between ‘CHOPN’ molecules: those composed of carbon, hydrogen, oxygen, phosphorus and nitrogen atoms, with phosphorus being present only in phosphate groups[21,22]
We have identified many alternatives to perhaps the most highly conserved set of metabolic reactions, the glycolytic and gluconeogenic trunk pathways
Summary
The universality of many pathways of core metabolism suggests a strong role for evolutionary selection, but it remains unclear whether existing pathways have been selected from a large or small set of biochemical possibilities To address this question, we construct in silico all possible biochemically feasible alternatives to the trunk pathway of glycolysis and gluconeogenesis, one of the most highly conserved pathways in metabolism. A very small number of variations are observed in nature (see Supplementary Discussion for details) The existence of such an ancient and universal pathway suggests three possible scenarios: (i) the trunk pathway is the only biochemical possibility, (ii) alternatives exist but the extant pathway is evolutionarily optimal and (iii) alternatives are possible but have not been found by evolution. By systematically constructing and exploring the full space of biochemically feasible metabolites and reactions, many of which are not currently exploited by any
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