(23c) Metabolomics and Isotope Tracing Reveal the Dynamic Role of Parallel Glycolytic Pathways

Glycolysis is a highly conserved pathway for the production of energy and biomass. However, some organisms simultaneously express the parallel Entner-Doudoroff (ED) pathway. The ED pathway yields only half as many ATP as textbook glycolysis, and the role of this seemingly less efficient pathway remains unclear. Here, we demonstrate that the ED pathway supports cell growth by rapid acceleration of glycolysis. We developed an isotope tracing strategy to quantify the distribution of glycolytic pathways during dynamic metabolic responses to changes in nutrient environment. While ED pathway utilization is low in the nutrient limited state, flux through the ED pathway increases disproportionately higher than textbook glycolysis upon nutrient upshifts. Consequently, the two pathways jointly increase total glycolytic flux to more rapidly increase cellular growth rate. Intermittent feeding of a limiting nutrient showed that the strain with both glycolytic pathways achieve higher cell densities than its ED-knockout counterpart. Thus, organisms with parallel yet specialized pathways can rapidly accelerate metabolism and growth, netting an edge over those with less metabolic flexibility. We surmise that the benefits of parallel pathways play a role in the holistic design of metabolic systems and that organisms may employ similar strategies elsewhere in metabolism.