6phosphofructo2kinase

6-phosphofructo-2-kinase, commonly referred to as phosphofructokinase-2 (PFK-2), is a bifunctional enzyme that regulates cellular glycolysis and gluconeogenesis by controlling the levels of fructose-2,6-bisphosphate (F2,6BP). The enzyme possesses two activities on a single polypeptide: a kinase activity that converts fructose-6-phosphate to fructose-2,6-bisphosphate and a phosphatase activity that degrades fructose-2,6-bisphosphate back to fructose-6-phosphate. Fructose-2,6-bisphosphate is a potent allosteric activator of phosphofructokinase-1 (PFK-1) and an inhibitor of fructose-1,6-bisphosphatase, so rising F2,6BP levels promote glycolysis while suppressing gluconeogenesis.

In mammals, PFK-2/FBPase-2 activity is encoded by four PFKFB genes (PFKFB1–PFKFB4), which generate tissue-specific isozymes with different ratios of kinase to phosphatase activity. This variation allows tissues to tune F2,6BP production in response to hormonal signals and energetic status. Regulation frequently occurs through phosphorylation: protein kinase A (PKA)–mediated phosphorylation typically reduces kinase activity and increases phosphatase activity, lowering F2,6BP and favoring gluconeogenesis, notably in the liver during fasting. Conversely, insulin signaling promotes dephosphorylation and higher F2,6BP levels, promoting glycolysis.

The enzyme is cytosolic and broadly expressed, with certain isoforms enriched in liver, heart, brain, or other tissues. In pathology, overexpression of some PFKFB isoforms, particularly PFKFB3, is observed in many cancers and is associated with enhanced glycolytic flux; such dysregulation is being explored as a potential therapeutic target.