5. Regulation and disorders of carbohydrate metabolism

Last updated on November 19, 2018 at 17:16

Summary

  • AMP dependent protein kinase is an enzyme that is activated by high [AMP], which activates processes that yield ATP, and inhibit processes that use ATP for non-essential processes.
  • Glucokinase is regulated by moving it in and out of the cytosol, where it is used.
  • Regulation is summed up here

AMP dependent protein kinase

This enzyme is activated by an increase in [AMP]. [AMP] is increased as the level of ATP in the cell decreases, either as a cause of exercise or not enough nutrition. AMPK then phosphorylates many different key proteins, regulating their activity to either increase their activity (if their activity causes an increase in ATP, for example beta oxidation), or decrease their activity (if their activity causes a decrease in ATP, for example gluconeogenesis).

How AMP dependent protein kinase regulates different metabolic processes.

Regulation of glucokinase

There are 4 different isotypes of the hexokinase enzyme. Hexokinase type 4 is only found in liver, and is often called glucokinase, as it is specific for glucose and not for other hexoses. The first 3 types are found elsewhere and are often referred to as just hexokinase. The latter is inhibited by its product, G6P, while glucokinase isn’t.

You can read more about glucokinase here.

The regulation of phosphofructokinase-1 and fructose 1,6-bisphosphatase is reciprocal

 

How PFK-1 and FBPase-1 are regulated. Note that the effect of fructose 2,6-bisphosphate is missing from this figure for some reason. Why, Lehninger?

Reciprocal means oppositely regulated; when one is activated, the other is inhibited. This is done to prevent the gluconeogenesis and glycolysis from running at the same time, which would waste energy. PFK-1 belongs to glycolysis, while FBPase-1 belongs to gluconeogenesis.

Looking at the figure above, let’s look at citrate as an example of how it works. Citrate is an intermediate in the citric acid cycle (hence the name), and works as a signal to tell enzymes that the cell doesn’t need more ATP right now. This is why it inhibits PFK-1, so it pushes the equilibrium towards gluconeogenesis instead of glycolysis.

Fructose 2,6-bisphosphate also regulates things

The effect of fructose 2,6-bisphosphate on PFK-1 and FBPase-1.

Fructose 2,6-bisphosphate is the most potent regulator of PFK-1 and FBPase-1. It mediates how insulin and glucagon controls the the balance between glycolysis and gluconeogenesis. The presence of F26BP in the cell is a glycolytic signal, which means it will push the cell to do more glycolysis and less gluconeogenesis. When F26BP levels drop, the cell will do more gluconeogenesis and less glycolysis. F26BP is produced when the cell needs it. Let’s see how.

The effect of insulin and glucagon on PFK-2 and FBPase-2. Note that the “phosphoprotein phosphatase” is actually Phosphoprotein Phospatase 1, or PP1. The “cAMP-dependent protein kinase” is actually Protein Kinase A (PKA).

Fructose 2,6-bisphosphate is produced from fructose 6-phosphate by phosphofructokinase-2. The reverse reaction is catalysed by fructose 2,6-bisphosphatase. PFK-2 and FBPase-2 are oppositely regulated by PP1 and PKA.

Because PFK-2 and FBPase-2 catalyse the opposite reactions, they are reciprocally activated and inactivated. Insulin, which signals a cell to do more glycolysis and less gluconeogenesis, activates PP1. The activation of PP1 causes the activation of PFK-2 and the inactivation of FBPase-2. This activation of PFK-2 causes formation of fructose 2,6-bisphosphate, which activates PFK-1, which activates the glycolysis. Long pathway, right?

Glucagon works oppositely. Glucagon activates PKA, which activates FBPase-2 and inactivates PFK-2, which catalyses the removal of cellular F26BP by converting it into F6P, which removes its activation of PFK-1, which indirectly activates gluconeogenesis.

Regulation of pyruvate kinase

Pyruvate kinase is inhibited by ATP, acetyl-CoA and long-chain fatty acids. This makes sense, as all three of these are present when the body has enough energy, so pyruvate kinase shouldn’t be needed.

In the liver, it is also regulated by hormones. Glucagon (the hormone that tells the liver to stop using glucose for itself and instead release it into the blood) inactivates pyruvate kinase to stop glycolysis. Insulin activates it.

Role of Acetyl-CoA in regulation

Acetyl-CoA inhibits pyruvate dehydrogenase complex as a negative feedback mechanism. It also activates pyruvate carboxylase, which is used to push the equilibrium between glycolysis/gluconeogenesis slightly toward gluconeogenesis.

How acetyl-CoA regulates things.


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4. Regulation of glycogen synthesis and degradation

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6. Fatty acid synthesis (with elongation and desaturation)

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