From the Research
Fructose-2,6-bisphosphate is the key metabolite that allosterically activates phosphofructokinase-1 (PFK-1), a rate-limiting enzyme in glycolysis, to increase glycolytic activity in the liver. This metabolite is produced by the bifunctional enzyme phosphofructokinase-2/fructose bisphosphatase-2 (PFK-2/FBPase-2), which responds to hormonal and nutritional signals 1. When fructose-2,6-bisphosphate binds to PFK-1, it causes a conformational change that increases the enzyme's affinity for its substrate fructose-6-phosphate while decreasing inhibition by ATP. This activation overcomes the inhibitory effects of other metabolites like citrate and ATP, effectively committing glucose to the glycolytic pathway. The concentration of fructose-2,6-bisphosphate increases in the fed state when insulin levels are high, promoting glycolysis, and decreases during fasting when glucagon predominates, shifting metabolism toward gluconeogenesis 2, 3, 4, 5. This regulatory mechanism allows the liver to rapidly adjust its metabolic activity based on the body's energy needs. Some key points to consider include:
- Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth 1
- The PFKFB4 expressed in multiple transformed cells and tumors functions to synthesize F2,6BP, and its inhibition may have clinical utility for the treatment of human cancers 1
- The structure of the synthetic kinase, conjoined at its carboxyl-terminus to the phosphatase, is very highly conserved throughout evolution and differentiation, with isotypic expression arising from highly variable amino-terminal and carboxyl-terminal regulatory domains 5