Figure 3.

Fructose metabolism and the mechanism for reducing intracellular ATP levels. Fructose is first phosphorylated to fructose-1-phosphate by KHK-C, leading to a rapid consumption of ATP that is directly dependent on the concentration of fructose. Unlike glucose, which never sees a substantial decrease in ATP, the KHK-C driven reaction can plummet both ATP and intracellular phosphate concentrations. In turn, the low intracellular phosphate triggers activation of AMP deaminase-2 (AMPD2). AMP generated during the depletion of ATP is then metabolized to inosine monophosphate (IMP) and eventually to uric acid. The utilization of AMP removes some of the AMP substrate needed to regenerate ATP. However, the intracellular uric acid stimulates NADPH oxidase that translocates to the mitochondria, while simultaneously inhibiting the mitochondrial antioxidant protective mechanisms, particularly Nrf-2. The mitochondrial oxidative stress inhibits both mitochondrial beta fatty acid oxidation (inhibiting enoyl CoA hydratase) and the tricarboxylic acid cycle (by blocking aconitase) resulting in suppression of ATP production by oxidative phosphorylation. In addition, the uric acid also inhibits AMP-activated protein kinase (AMPK) that helps regenerate ATP in low energy states. Thus, the net effect of fructose metabolism KHK-C is that it will reduce intracellular ATP levels. (Online version in colour.)