Phosphofructokinase2

Phosphofructokinase-2 (PFK-2) is a bifunctional enzyme that regulates cellular metabolism by controlling the levels of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. In mammals, PFK-2 activity is part of the PFKFB gene family, with four main isoforms (PFKFB1–PFKFB4) that are expressed in tissue-specific patterns. Each PFK-2/FBPase-2 protein contains two catalytic domains: a fructose-6-phosphate kinase domain that produces F2,6BP from fructose-6-phosphate, and a fructose-2,6-bisphosphatase domain that degrades F2,6BP back to fructose-6-phosphate. The net concentration of F2,6BP thereby tunes the activity of phosphofructokinase-1 (PFK-1) and, consequently, the glycolytic flux.

Regulation of PFK-2 is influenced by tissue context and hormonal signaling. In the liver, glucagon elevates cAMP and activates protein kinase A, which phosphorylates PFK-2 and shifts its activity toward the phosphatase function, lowering F2,6BP and downregulating glycolysis while promoting gluconeogenesis. In contrast, insulin signaling promotes dephosphorylation, increasing F2,6BP and enhancing glycolysis. The different PFKFB isoforms exhibit varying kinase-to-phosphatase activity ratios, shaping their metabolic effects in liver, heart, kidney, adipose tissue, and other sites.

Clinical relevance includes the association of PFKFB3 upregulation with enhanced glycolysis in many cancers, linking PFK-2 activity to the Warburg effect. As a regulator of a key glycolytic switch, PFK-2 is studied as a potential target for therapies addressing metabolic diseases and cancer.

In summary, PFK-2 is a dual-function enzyme that mediates metabolic decisions between glycolysis and gluconeogenesis by modulating fructose-2,6-bisphosphate levels in response to cellular and hormonal signals.