Glycolysis: Control of flux

The flux through the glycolytic pathway must be adjusted in response to conditions both inside and outside the cell. The rate is regulated to meet two major cellular needs: (1) the production of ATP, and (2) the provision of building blocks for biosynthetic reactions. In glycolysis, the reactions catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase are effectively irreversible. In metabolic pathways, such enzymes are potential sites of control, and all these three enzymes serve this purpose in glycolysis.

There are several different ways to regulate the activity of an enzyme. An immediate form of control is feedback via allosteric effectors or by covalent modification. A slower form of control is transcriptional regulation that controls the amounts of these important enzymes.

Hexokinase

Hexokinase is inhibited by glucose-6-phosphate (G6P), the product it forms through the ATP driven phosphorylation. This is necessary to prevent an accumulation of G6P in the cell when flux through the glycolytic pathway is low. Glucose will enter the cell but since the hexokinase is not active it can readily diffuse back to the blood through the glucose transporter in the plasma membrane. If hexokinase remained active during low glycolytic flux the G6P would accumulate and the extra solute would cause the cells to enlarge due to osmosis.

In liver cells, the extra G6P is stored as glycogen. In these cells hexokinase is not expressed, instead glucokinase catalyses the phosphorylation of glucose to G6P. This enzyme is not inhibited by high levels of G6P and glucose can still be converted to G6P and then be stored as glycogen. This is important when blood glucose levels are high. During hypoglycemia the glycogen can be converted back to G6P and then converted to glucose by a liver specific enzyme glucose 6-phosphatase. This reverse reaction is an important role of liver cells to maintain blood sugars levels during fasting. This is critical for neuron function since they can only use glucose as an energy source.

Phosphofructokinase-1

Phosphofructokinase is an important control point in the glycolytic pathway since it is immediately downstream of the entry points for hexose sugars.

High levels of ATP inhibit the PFK enzyme by lowering its affinity for F6P. ATP causes this control by binding to a specific regulatory site that is distinct from the catalytic site. This is a good example of allosteric control. AMP can reverse the inhibitory effect of ATP. A consequence is that PFK is tightly controlled by the ratio of ATP/AMP in the cell. This makes sense since these molecules are direct indicators of the energy charge in the cell.

Since glycolysis is also a source of carbon skeletons for biosynthesis, a negative feedback control to glycolysis from the carbon skeleton pool is useful. Citrate is an example of a metabolite that regulates phosphofructokinase by enhancing the inhibitory effect of ATP. Citrate is an early intermediate in the citric acid cycle, and a high level means that biosynthetic precursors are abundant.

Low pH also inhibits phosphofructokinase activity and prevents the excessive rise of lactic acid during anaerobic conditions that could otherwise cause a drop in blood pH (acidosis).

Fructose 2,6-bisphosphate (F2,6BP) is a potent activator of phosphofructokinase (PFK-1) that is synthesised when F6P is phosphorylated by a second phosphofructokinase (PFK2). This second enzyme is inactive when cAMP is high, and links the regulation of glycolysis to hormone activity in the body. Both glucagon and adrenalin cause high levels of cAMP in the liver. The result is lower levels of liver fructose 2,6-bisphosphate such that gluconeogenesis (glycolysis in reverse) is favored. This is consistent with the role of the liver in such situations since the response of the liver to these hormones is to releases glucose to the blood.

Pyruvate kinase

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