Energy metabolism - Part 3: How is glycolysis regulated?
In the last episode, we introduced the three key enzymes of glycolysis.
These are hexokinase, phosphofructokinase 1, and pyruvate kinase.
So, why are they key enzymes?
Well, it's because they're important regulatory enzymes in glycolysis, and, can, therefore,
adapt the glycolytic process to meet the physiological needs of the body.
Enzyme activity can be regulated hormonally, via signaling molecules such as cAMP, as well
as allosterically.
Allosteric regulators are usually a product or reactant of the reaction and induce conformational
changes of the enzyme, thereby altering the enzyme activity.
We’ll encounter all these regulatory mechanisms in glycolysis.
Now, let’s start with the most important regulatory factors:
First, let’s look at hexokinase.
The hormone glucagon inhibits the transcription of hexokinase, and, thereby, the first step
of glycolysis.
Consequently, blood glucose levels increase.
In contrast, insulin facilitates the activity of glucose transporters and the transcription
of hexokinase.
The former increases glucose uptake into the cells, whereas the latter activates the first
step of glycolysis.
In this way, insulin significantly affects the decrease in blood glucose levels.
Another inhibitor for hexokinase is its product, glucose-6-phosphate.
It ensures that only a moderate amount of glucose-6-phosphate is produced in the cell.
An additional determining factor for the fine-tuning of glycolysis is the glucose affinity of the
various tissue-specific hexokinases.
Hexokinase IV, also termed glucokinase, which is present in the liver, has a low affinity
for glucose.
Hexokinases of other tissues have a higher glucose affinity.
This ensures that at low glucose concentrations, extrahepatic tissues are preferably supplied.
Only if there’s a high blood glucose concentration in the portal vein, the liver begins to store
glucose as glycogen.
The regulation of phosphofructokinase 1 has a major impact on glycolysis, as it is the
rate-limiting step.
Phosphofructokinase 1 is inhibited by three factors: ATP, citrate, and protons.
ATP leads to inhibition because it indicates that the cellular energy supply is sufficient.
Citrate accumulates in the first step of the citric acid cycle if there’s excess acetyl-coA
substrate.
Since glycolysis also contributes to acetyl-coA production, reducing the breakdown of glucose
helps in this case.
Therefore, citrate inhibits phosphofructokinase 1.
The third factor is an elevated proton concentration, or in other words, an acidic pH.
The pH decreases especially during the downstream anaerobic metabolism of pyruvate.
To prevent extreme and potentially cell damaging decreases, the glycolytic production of pyruvate
is inhibited at a low pH.
Now, phosphofructokinase 1 is activated by AMP.
The presence of AMP in the cell implies that energy is required.
It signifies a metabolic state in which glycolysis needs to be activated.
AMP, therefore, counterbalances enzyme inhibition by ATP.
In addition, fructose 2,6-bisphosphate can activate phosphofructokinase.
However, the underlying mechanism is somewhat complicated: Fructose 2,6-bisphosphate is
not an intermediate of glycolysis or another energy metabolism process, though it probably
strongly reminds you of fructose 1,6-bisphosphate.
Although both molecules are very similar and only differ in the position of one phosphate
group, they are not interconverted.
Let’s look at what’s important in this context: The activation of phosphofructokinase
1 by fructose 2,6-bisphosphate helps in the tissue-specific, hormonal regulation of glycolysis.
This regulation is triggered by increasing or decreasing cAMP levels.
So, for example, in a catabolic state, glucagon is released, elevating cAMP levels in the
liver.
This decreases the concentration of fructose 2,6-bisphosphate in the liver and inhibits
glycolysis.
In the heart however, increasing cAMP levels can be caused, for example, by the hormone
adrenaline, which is released under conditions of increased energy demand.
In this case, cAMP results in an increase of fructose-2,6-bisphosphate levels, therefore
stimulating glycolysis.
This ensures that glycolysis primarily covers the energy demands in vital organs such as
the heart, while the energy supply of less important organs, such as the liver, is reduced.
If you'd like to find out more, just click on the link which will take you to the corresponding
information in our library.
The regulation of pyruvate kinase is again somewhat easier to understand.
The last step of glycolysis is inhibited, for one, by ATP.
Again, ATP serves as a signal that the cell’s energy requirements are met.
Also, the amino acid alanine inhibits pyruvate kinase.
Alanine can be produced from pyruvate and signals that the substrate requirements of
other metabolic pathways are covered, similar to the effect of citrate for phosphofructokinase
1.
Pyruvate kinase is activated by the glycolytic intermediate fructose 1,6-bisphosphate.
This helps adapt the rate of glycolysis to the amount of substrate available.
Now, you’re probably wondering under what circumstances you’ll encounter glycolysis
as a physician in clinical practice: In fact, there are only very few conditions that are
directly associated with glycolysis.
This pathway is such a central part of the cell’s energy metabolism that defects are
usually incompatible with life.
The most common disorder encountered is pyruvate kinase deficiency.
It especially affects cells depending on glycolysis for their energy supply.
These include erythrocytes, which do not possess mitochondria and are, therefore, unable to
generate ATP by the electron transport chain.
Pyruvate kinase deficiency results in anemia with low hemoglobin levels.
In this particular case, however, the low hemoglobin level is better tolerated by the
patient in this type of anemia than in others.
So, how can this be explained?
The inhibition of the final step of glycolysis also causes an accumulation of substrates
in upstream reactions, including an increase of 1,3-bisphosphoglycerate.
Not only is this molecule an intermediate of glycolysis, but also a precursor to 2,3-bisphosphoglycerate.
2,3-bisphosphoglycerate is formed via the 2,3-bisphosphoglycerate shunt and is an important
regulator of the oxygen affinity of hemoglobin.
So, excess 1,3-bisphosphoglycerate in glycolysis increases the production of 2,3-bisphosphoglycerate,
therefore facilitating oxygen release from hemoglobin into the tissue.
In consequence, low hemoglobin levels are less harmful to the patient than in other
forms of anemia.
Other clinically relevant scenarios include disturbed metabolic pathways upstream or downstream
of glycolysis.
These include defects in glycogen assembly and degradation, which occur upstream of glycolysis.
It also includes the disturbed conversion of pyruvate following glycolysis.
Information on the disorders mentioned here can be found in the corresponding learning
cards.
Now, in this episode, we showed you crucial regulatory factors of glycolysis.
Let’s summarize the most important aspects:
Glycolysis regulation ensures that there are sufficient amounts of important substrates
in the cell.
Physiologically opposing metabolic processes are coordinated so that they don’t work
against each other, expending energy.
The slowest and, therefore, the rate-limiting step in glycolysis is step 3.
Hence, the regulation of phosphofructokinase 1 is especially important for glycolysis.
Hexokinase is activated by insulin and inhibited by glucose-6-phosphate and glucagon.
Phosphofructokinase 1 is activated by AMP and fructose 2,6-bisphosphate and inhibited
by ATP, citrate, and low pH levels.
Pyruvate kinase is activated by fructose 1,6-bisphosphate and inhibited by ATP and alanine.
In the quiz on the next slide, you can test your knowledge and see whether you’ve understood
which regulator signifies the metabolic state shown.