Flux Control in Glycolysis Varies Across the Tree of Life

Biochemical thought posits that rate-limiting steps (defined here as points of flux control) are strongly selected as points of pathway regulation and control and are thus expected to be evolutionarily conserved. Conversely, population genetic thought based upon the concepts of mutation-selection-drift balance at the pathway level might suggest variation in flux controlling steps over evolutionary time. Glycolysis, as one of the most conserved and best characterized pathways, was studied to evaluate its evolutionary conservation. The flux controlling step in glycolysis was found to vary over the tree of life. Further, phylogenetic analysis suggested at least 60 events of gene duplication and additional events of putative positive selection that might alter pathway kinetic properties. Together, these results suggest that even with presumed largely negative selection on pathway output on glycolysis, the co-evolutionary process under the hood is dynamic.