Phosphofructokinase-2/Fructose Bisphosphatase-2

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) is a bifunctional enzyme wherein a single polypeptide chain contains two enzymatic activities: PFK-2 and FBPase-2. PFK-2 catalyzes the transfer of phosphate from adenosine triphosphate to the second carbon (C-2) of fructose-6-phosphate (F6P), an intermediate in the glycolytic pathway, generating fructose-2,6-bisphosphate (F2,6BP). Conversely, FBPase-2 catalyzes the dephosphorylation of F2,6BP resulting in the liberation of free inorganic phosphate and regeneration of F6P. In this manner, these two physically linked enzymes function to modulate the cellular concentration of F2,6BP. The importance of this regulation cannot be understated as this sugar plays an essential signaling role in regulating glucose metabolism in a variety of tissues. Perhaps most importantly, it is largely responsible for regulating the balance between glycolysis and gluconeogenesis in the liver. This balance, critical to maintaining blood glucose levels within the normal range regardless of the nutritional state, principally results from the fact that F2,6BP activates a key regulatory glycolytic enzyme, 6-phosphofructo-1-kinase, and inhibits a regulatory enzyme in gluconeogenesis, fructose-1,6-bisphosphatase. In the liver, therefore, when F2,6BP levels are high, glycolysis predominates; when F2,6BP levels are low, gluconeogenesis predominates. In other tissues, F2,6BP levels mainly serve to help regulate glycolytic flux. By regulating the level of this phosphorylated sugar, PFK-2/FBPase-2 activities play a central role in maintaining glucose homeostasis and utilization.