The regulation of two key enzymes, PFK-1 and FBPase-1, is crucial in the balance between glycolysis and gluconeogenesis. PFK-1 facilitates the conversion of F6P to F-1,6-BP during glycolysis, while FBPase-1 catalyzes the reverse reaction during gluconeogenesis. The activity of these enzymes is directly regulated by fructose-2,6-bisphosphate (F-2,6-BP), which activates PFK-1 and inhibits FBPase-1.
The production of F-2,6-BP is controlled by phosphofructokinase-2 (PFK-2) and FBPase-2, which are part of the same bifunctional enzyme. PFK-2 generates F-2,6-BP, while FBPase-2 converts F-2,6-BP back to F6P. Protein kinase A, or PKA, regulates the activity of PFK-2 and FBPase-2, ensuring that only one is active at a time. In the fed state, insulin increases intracellular glucose uptake, inhibiting adenylate cyclase, resulting in decreased cyclic AMP and protein kinase A, ultimately leading to the activation of PFK-1 and glycolysis. During fasting, intracellular glucose levels decrease, leading to the activation of adenylate cyclase, increased cyclic AMP and protein kinase A, and subsequently the activation of FBPase-1 and gluconeogenesis.
<ul> <li>PFK-1 and FBPase-1 <ul> <li>PFK-1: Transfers P-battery to F6P pirate’s “1” pegleg, producing F-1,6-BP</li> <li>FBPase-1: Removes P-battery from F-1,6-BP pirate’s “1” pegleg, producing F6P</li> <li>Role in glycolysis and gluconeogenesis</li> </ul> </li> <li>Regulation by F-2,6-BP <ul> <li>Activates PFK-1 and inhibits FBPase-1</li> </ul> </li> <li>PFK-2 and FBPase-2 <ul> <li>PFK-2: Transfers phosphate group from ATP to F6P, producing F-2,6-BP</li> <li>FBPase-2: Catalyzes opposite reaction, converting F-2,6-BP back to F6P</li> <li>Both part of the same bifunctional enzyme</li> </ul> </li> <li>Protein kinase A (PKA) <ul> <li>Switch that activates FBPase-2 and deactivates PFK-2</li> <li>Levels regulated by cyclic AMP (high cAMP, high protein kinase A)</li> </ul> </li> <li>Fed state <ul> <li>Increased blood glucose levels trigger insulin release, inhibiting adenylate cyclase and resulting decrease in cyclic AMP and protein kinase A (PKA)</li> <li>Insulin activates PFK-2, producing more F-2,6-BP</li> <li>Increased F-2,6-BP activates PFK-1 and glycolysis</li> </ul> </li> <li>Fasting state <ul> <li>Low blood glucose levels trigger glucagon release</li> <li>Glucagon activates adenylate cyclase, producing more cyclic AMP</li> <li>High cyclic AMP levels activate protein kinase A and FBPase-2</li> <li>Decreased F-2,6-BP results in activated FBPase-1 and gluconeogenesis</li> </ul> </li> </ul>
PFK-1 (Phosphofructokinase-1) plays a crucial role in glycolysis regulation as it serves as the rate-limiting enzyme in the glycolytic pathway. PFK-1 catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. The activity of PFK-1 is regulated by factors such as ATP, AMP, citrate, and fructose-2,6-bisphosphate (F-2,6-BP), allowing it to respond to the cell's energy demands and maintain proper metabolic balance.
Fructose-2,6-bisphosphate (F-2,6-BP) is a crucial regulator of both glycolysis and gluconeogenesis. F-2,6-BP activates PFK-1, promoting glycolysis by increasing the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Conversely, F-2,6-BP inhibits FBPase-1 (fructose-1,6-bisphosphatase), reducing the conversion of fructose-1,6-bisphosphate back to fructose-6-phosphate in gluconeogenesis. This dual action of F-2,6-BP ensures a reciprocal regulation of glycolysis and gluconeogenesis depending on cellular needs.
PFK-2 (Phosphofructokinase-2) and FBPase-2 (Fructose-2,6-bisphosphatase) are two activities of the same bifunctional enzyme that regulate the levels of fructose-2,6-bisphosphate (F-2,6-BP) in the cell. PFK-2 is responsible for the synthesis of F-2,6-BP by converting fructose-6-phosphate to F-2,6-BP, while FBPase-2 catalyzes the reverse reaction, converting F-2,6-BP back to fructose-6-phosphate. The balance between the two activities determines the intracellular concentration of F-2,6-BP, which in turn regulates glycolysis and gluconeogenesis.
Protein kinase A (PKA) is a critical component in the regulation of glycolysis and gluconeogenesis through its effect on the bifunctional enzyme PFK-2/FBPase-2. Activation of PKA leads to the phosphorylation of PFK-2/FBPase-2, which inhibits the PFK-2 activity and activates the FBPase-2 activity. As a result, F-2,6-BP levels decrease, inhibiting glycolysis by reducing PFK-1 activity and promoting gluconeogenesis by relieving the inhibition on FBPase-1.