6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3)

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a bifunctional enzyme responsible for both the synthesis and degradation of fructose-2,6-bisphosphate, a key regulator of glucose metabolism in mammals. It participates in both glycolysis (via its kinase activity) and gluconeogenesis (via its bisphosphatase activity), and is highly inducible, especially in rapidly proliferating cells like tumor cells. The enzyme has a much higher kinase-to-phosphatase activity ratio than other family members, strongly favoring the generation of fructose-2,6-bisphosphate and thus promoting glycolytic flux. PFKFB3 activity is also essential for cell cycle progression and cell survival, linking metabolic control to cell proliferation and apoptosis prevention. Overexpression of PFKFB3 is frequently observed in cancer, where it supports the metabolic demands of tumor growth and is regulated by factors such as hypoxia-inducible factor-1 alpha (HIF-1α). As such, PFKFB3 is under investigation as a therapeutic target in oncology and metabolic disease.

Inhibition of PFKFB3 lowers fructose-2,6-bisphosphate levels, reducing glycolytic flux, arresting the cell cycle, and promoting apoptosis, particularly in cancer cells