The Warburg Effect is the result of faster ATP production by glycolysis than respiration

Many prokaryotic and eukaryotic cells choose to partially metabolize glucose to organism-specific byproducts instead of fully oxidizing it to carbon dioxide and water, even in the presence of oxygen. This phenomenon was originally observed in tumor cells and is often referred to as the Warburg Effect. The benefit to a cell has been unclear, given that partial metabolism of glucose yields an order of magnitude less ATP per molecule of glucose than complete oxidation. Here, we propose and test the hypothesis that the Warburg Effect stems from the optimization of energy metabolism that allows cells to produce ATP at the highest possible rate in the presence of excess glucose independent of cell growth rate. To test our hypothesis, we estimated the yield, specific activity, and proteome occupancy of various versions of the glycolysis and respiration pathways in three different organisms. We found that organism-specific glycolytic pathways produce ATP at a 1.1-1.5 (E. coli), 1.4-2.0 (S. cerevisiae), and 2-4.8-fold (mammalian cells) faster rate per gram of pathway protein than respective respiration pathways. For E. coli, only the respiro-fermentative Pta-AckA version of glycolysis, not fermentative glycolysis, produced ATP faster than respiration, explaining the preference for the Pta-AckA pathway in the presence of oxygen. We then showed that a simple mathematical model that takes these estimates as the only inputs (i.e., model has no free parameters) can accurately predict absolute rates of glycolysis byproduct secretion and respiration in E. coli, S. cerevisiae, and mammalian cells under a variety of conditions irrespective of growth rate. Taken together, our study suggests that the Warburg Effect is a manifestation by which cells optimize the rate of energy generation.