A parallel glycolysis supports rapid adaptation in dynamic environments

Glycolysis is a universal metabolic process that breaks down glucose to produce cellular energy currency ATP and biomass precursors[1][1]. The Entner-Doudoroff pathway is a glycolytic pathway that parallels the textbook glycolysis but yields half as many ATP[2][2]. In organisms that possess both glycolytic pathways, such as Escherichia coli , inactivating the less energy-efficient Entner-Doudoroff pathway does not alter growth rates[3][3]. The benefit of the Entner-Doudoroff pathway has instead been hypothesized to be metabolic flexibility as an auxiliary enzyme-efficient catabolic route[4][4]. However, its raison d’être remains incompletely understood. Here we identify the advantage of employing parallel glycolytic pathways under dynamic nutrient environments. Upon carbon and nitrogen upshifts, wild-type cells accelerate growth faster than those with the Entner-Doudoroff pathway knocked out. Using stable isotope tracers and mass spectrometry, we find that the Entner-Doudoroff pathway flux increases disproportionately faster than that of the textbook glycolysis during nutrient upshifts. We attribute the fast response time of the Entner-Doudoroff pathway to its strong thermodynamic driving force and concerted regulation facilitating glucose uptake. Intermittent supply of nutrients manifests this evolutionary advantage of the parallel glycolysis. Thus, the dynamic nature of an ostensibly redundant pathway’s role in promoting rapid adaptation constitutes a metabolic design principle. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4