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

Many prokaryotic and eukaryotic cells metabolize glucose to organism-specific by-products instead of fully oxidizing it to carbon dioxide and water-a phenomenon referred to as the Warburg Effect. The benefit to a cell is not fully understood, given that partial metabolism of glucose yields an order of magnitude less adenosine triphosphate (ATP) per molecule of glucose than complete oxidation. Here, we test a previously formulated hypothesis that the benefit of the Warburg Effect is to increase ATP production rate by switching from high-yielding respiration to faster glycolysis when excess glucose is available and respiration rate becomes limited by proteome occupancy. We show that glycolysis produces ATP faster per gram of pathway protein than respiration in <i>Escherichia coli</i>, <i>Saccharomyces cerevisiae</i>, and mammalian cells. We then develop a simple mathematical model of energy metabolism that uses five experimentally estimated parameters and show that this model can accurately predict absolute rates of glycolysis and respiration in all three organisms under diverse conditions, providing strong support for the validity of the ATP production rate maximization hypothesis. In addition, our measurements show that mammalian respiration produces ATP up to 10-fold slower than respiration in <i>E. coli</i> or <i>S. cerevisiae</i>, suggesting that the ATP production rate per gram of pathway protein is a highly evolvable trait that is heavily optimized in microbes. We also find that <i>E. coli</i> respiration is faster than fermentation, explaining the observation that <i>E. coli</i>, unlike <i>S. cerevisiae</i> or mammalian cells, never switch to pure fermentation in the presence of oxygen.