Glycolysis is regulated through a combination of allosteric control, covalent modification, and hormonal regulation, primarily targeting three key enzymes: hexokinase, phosphofructokinase-1 (PFK-1), and pyruvate kinase.
Allosteric Regulation
Allosteric regulation involves the binding of molecules (allosteric effectors) to enzymes, which alters their conformation and, consequently, their activity. This provides immediate, moment-to-moment control over glycolytic flux.
Hexokinase
- Inhibition: Hexokinase is inhibited by its product, glucose-6-phosphate (G6P). High levels of G6P signal that the cell doesn't need more glucose for energy or storage and can feedback inhibit the enzyme.
- Isozymes: In the liver, glucokinase (hexokinase IV) is not inhibited by G6P. It has a lower affinity for glucose than other hexokinases, allowing the liver to process high glucose levels without inhibiting glucose uptake in other tissues.
Phosphofructokinase-1 (PFK-1)
PFK-1 is the most important regulatory enzyme in glycolysis.
- Activation:
- AMP and ADP: Indicate low energy charge and stimulate PFK-1 activity.
- Fructose-2,6-bisphosphate (F2,6BP): A potent allosteric activator of PFK-1, overriding the inhibition by ATP. F2,6BP levels are controlled by the bifunctional enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase (PFK-2/FBPase-2), which itself is regulated hormonally (see below).
- Inhibition:
- ATP: High levels of ATP indicate a sufficient energy supply and inhibit PFK-1.
- Citrate: Signals that the citric acid cycle is producing enough energy, further inhibiting PFK-1.
Pyruvate Kinase
- Activation:
- Fructose-1,6-bisphosphate (F1,6BP): The product of the PFK-1 reaction, acts as a feed-forward activator of pyruvate kinase.
- Inhibition:
- ATP: Indicates high energy charge and inhibits pyruvate kinase.
- Alanine: Signals sufficient amino acid supply and inhibits pyruvate kinase.
- Acetyl-CoA: Signals that the citric acid cycle is producing enough energy, further inhibiting pyruvate kinase.
Covalent Modification
Covalent modification involves the addition or removal of chemical groups to enzymes, altering their activity.
- Phosphorylation/Dephosphorylation: This is a common form of covalent modification. For example, in the liver, glucagon signals low blood glucose and triggers phosphorylation of pyruvate kinase, inhibiting its activity. Insulin has the opposite effect, promoting dephosphorylation and activation.
Hormonal Regulation
Hormones like insulin and glucagon influence glycolysis by regulating the expression of glycolytic enzymes and the levels of key regulatory molecules like fructose-2,6-bisphosphate.
- Insulin:
- Increases the expression of glucokinase, PFK-1, and pyruvate kinase.
- Activates PFK-2, increasing the levels of F2,6BP, which stimulates PFK-1.
- Glucagon:
- Decreases the expression of glucokinase, PFK-1, and pyruvate kinase.
- Inactivates PFK-2 (through phosphorylation), decreasing the levels of F2,6BP, which inhibits PFK-1.
Summary Table
| Enzyme | Activators | Inhibitors |
|---|---|---|
| Hexokinase | None (except Glucokinase) | Glucose-6-phosphate |
| Phosphofructokinase-1 | AMP, ADP, Fructose-2,6-bisphosphate | ATP, Citrate |
| Pyruvate Kinase | Fructose-1,6-bisphosphate | ATP, Alanine, Acetyl-CoA, Phosphorylation (in liver) |
Glycolysis is tightly controlled through a combination of allosteric regulation, covalent modification, and hormonal signals to meet the energy needs of the cell and the organism.
