PFK2

Phosphofructokinase-2 (PFK-2) is a bifunctional enzyme that modulates glycolysis by controlling the cellular level of fructose-2,6-bisphosphate (F2,6BP). In most organisms, PFK-2 exists as a domain of larger bifunctional proteins encoded by the PFKFB gene family (PFKFB1–PFKFB4 in mammals). Each isoform contains a kinase domain that synthesizes F2,6BP from fructose-6-phosphate and ATP, and a phosphatase domain that dephosphorylates F2,6BP back to F6P. The net kinase/phosphatase balance determines the steady-state F2,6BP concentration, which in turn regulates phosphofructokinase-1 (PFK-1) activity and hence glycolysis. F2,6BP is a potent allosteric activator of PFK-1 and an inhibitor of fructose-1,6-bisphosphatase, shifting metabolism toward glycolysis.

Isoforms vary in tissue distribution and in the relative activities of the kinase and phosphatase domains. In humans, the four PFKFB genes encode distinct bifunctional enzymes with different regulatory properties, allowing tissue-specific control of glycolytic flux.

Regulation is hormonally controlled. In liver, glucagon signaling elevates cAMP and protein kinase A, promoting phosphorylation of PFK-2/FBPase-2 and favoring the phosphatase activity, which lowers F2,6BP and reduces glycolysis while promoting gluconeogenesis. Insulin drives dephosphorylation, increasing kinase activity and raising F2,6BP to stimulate glycolysis.

Clinical relevance includes altered PFKFB expression in cancer, where high F2,6BP levels can support aerobic glycolysis and rapid growth, and in metabolic diseases where glycolytic control is disrupted. Research continues into selective modulators of PFK-2/FBPase-2 activity as potential therapies.