The Essence of Nature Can be the Simplest (1)--Warburg Effect: Transition from Intracellular ATP to Extracellular Fenton Chemistry.

Here we explain the energy mechanism behind the Warburg effect of aerobic glycolysis, which has been unsolved for a hundred years. We found that fungal cells that can engage in extracellular Fenton reactions share central carbon metabolism with cancer cells that can produce the Warburg effect. Fungal cells also undergo aerobic glycolysis, significantly reducing intracellular ATP levels and allocating large amounts of oxygen for the extracellular Fenton reactions. The use of aerobic glycolysis for the extracellular Fenton reaction can be a common phenomenon in nature, as glycolysis is a metabolic pathway that occurs in every cell. The development of extracellular Fenton reaction can be divided into rapid and slow formation. Rapid extracellular Fenton reactions occur predominantly in organisms that contain the key biosynthetic genes for secondary metabolite biosynthesis, while endotherms have limited capacity for slow extracellular reactions due to lack of these critical genes. Endogenous aromatic metabolites can initiate strong extracellular Fenton reactions and siderophores can sequester and recycle iron and protect the host from extracellular Fenton reactions. Most exogenous aromatics can induce an extracellular Fenton reaction reflux, thereby inhibiting cancer cells and pathogenetic microorganisms that exhibit stronger extracellular Fenton reactions than normal cells and non-pathogenetic microorganisms.