Energy metabolism Part 10 - What’s the difference between gluconeogenesis and glycolysis?
Why can we get by without food for several hours and don’t have to raid the fridge
at night?
After all, some cells only cover their energy needs with glucose and depend on a relatively
constant blood sugar level.
These include erythrocytes, which don’t possess mitochondria, or cells of the brain,
which don't absorb most fatty acids due to the blood-brain barrier.
For these cells, blood glucose levels shouldn’t drop too low, not even without eating for
several hours.
Therefore, the body starts to produce glucose once blood glucose levels fall below 70 mg/dL.
This process is termed gluconeogenesis, which means synthesis of new glucose.
As a substrate, gluconeogenesis mainly uses pyruvate, which comes from the breakdown of
lactate, glycolysis, or amino acid degradation.
Additionally, oxaloacetate from amino acid degradation and dihydroxyacetone phosphate,
in short DAP, from the breakdown of glycerol during lipid metabolism can be used in gluconeogenesis.
In other words, the body can synthesize glucose from noncarbohydrate precursors.
In the last Chalk Talk episode on the Cori cycle, we learned that gluconeogenesis primarily
occurs in the liver.
Though, it also takes place in the kidneys, brain, and cardiac or skeletal muscles, but
to a lesser extent.
Now, let's go through the process of glucose synthesis.
Glucose production is essentially the reversal of glucose breakdown.
Consequently, most reaction steps in gluconeogenesis are the reverse reactions of glycolysis.
So to understand gluconeogenesis, you should be familiar with the reactions occurring in
glycolysis.
Don’t forget that you can refresh your knowledge by watching episode 2 of our energy metabolism
course.
Now, there are a few important differences between the reactions of glycolysis and gluconeogenesis,
which we’ll delve into here.
If you’d like to see molecular structures with the names of the substances, then click
on Dieter’s red molecule.
You can hide the structures at any time by clicking on the molecule again.
Glycolysis and gluconeogenesis differ in only three reaction steps, namely those of the
key enzymes of glycolysis.
Because these reactions are irreversible in glycolysis, they can’t directly be reversed
for gluconeogenesis: At the beginning of gluconeogenesis, pyruvate
is converted into phosphoenolpyruvate in two steps via a small detour.
Accordingly, gluconeogenesis requires a total of 11 reaction steps instead of the 10 in
glycolysis.
Phosphoenolpyruvate is a high-energy compound.
This means it’s unstable and easily loses its phosphate group.
While the release of a large amount of energy during the formation of pyruvate from phosphoenolpyruvate
is advantageous in glycolysis, the corresponding conversion represents an obstacle in gluconeogenesis.
It requires a great deal of energy and can only proceed through an intermediate that’s
also rich in energy, namely oxaloacetate.
The initial formation of one molecule of oxaloacetate requires one ATP molecule.
Let’s take note of this in our energy balance.
Because a total of two pyruvate molecules are needed to produce one molecule of glucose,
the expenditure for this step needs to be doubled.
This first reaction step of gluconeogenesis is catalyzed by pyruvate carboxylase.
Subsequently, oxaloacetate is converted by phosphoenolpyruvate carboxykinase to phosphoenolpyruvate.
The decarboxylation of oxaloacetate, that is, the cleavage of its carboxylic acid group,
is strongly exergonic.
It provides the energy required for forming phosphoenolpyruvate.
However, the decarboxylation reaction again requires energy, which is provided in the
form of GTP.
For each molecule of glucose, two GTP molecules are consumed.
We’ll add these as well to our energy balance.
An important difference between glycolysis and gluconeogenesis is the reaction sites:
Glycolysis only occurs in the cytosol, while in gluconeogenesis, oxaloacetate is produced
in the mitochondrion.
Involving mitochondria makes sense, as oxaloacetate can be fed into the citric acid cycle, which
is also located in mitochondria.
The pyruvate carboxylase reaction, therefore, belongs to the replenishing reactions of the
citric acid cycle, which are technically termed anaplerotic reactions.
However, the formation of phosphoenolpyruvate and the gluconeogenetic reactions catalyzed
by the reversible enzymes of glycolysis occur once again in the cytosol.
For that, oxaloacetate must be transported from the mitochondrion into the cytosol.
We’ve partially introduced the responsible transport system in our episode on the electron
transport chain: the malate-aspartate shuttle.
In the following six reactions, phosphoenolpyruvate is converted to fructose-1,6-bisphosphate.
The reactions proceed analogously to their respective reverse reactions from glycolysis.
So, for the conversion of 3-phosphoglycerate to 1,3-bisphosphoglycerate, ATP is required.
Again, for each molecule of glucose, two additional molecules of ATP need to be deducted from
the energy balance.
The subsequent conversion of 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate requires one
reducing equivalent of NADH and H+, leading to a total expenditure of two NADH and H+
per glucose molecule.
The synthesis of fructose-6-phosphate in the ninth reaction is again carried out by an
enzyme specific to gluconeogenesis.
This is because phosphofructokinase 1 from glycolysis is a key enzyme and its reaction
thereby irreversible.
The enzyme responsible for converting fructose 1,6-bisphosphate to fructose 6-phosphate is
named according to its substrate: fructose 1,6-bisphosphatase.
The cleaved phosphate group isn’t used to form ATP.
So, this reaction doesn’t provide the cell with energy.
Fructose-1,6-bisphosphatase is one of the three key enzymes of gluconeogenesis.
The other two key enzymes are pyruvate carboxylase and phosphoenolpyruvate carboxykinase.
These enzymes regulate gluconeogenesis, as we’ll see in the next episode.
In the following step, fructose-6-phosphate is converted to glucose-6-phosphate by an
enzyme from glycolysis.
However, glucose-6-phosphate can’t be converted into glucose by hexokinase from glycolysis.
Instead, the eleventh and final reaction of gluconeogenesis is performed by glucose-6-phosphatase.
Although this enzyme is specific to gluconeogenesis, it’s not a key enzyme in the process.
It’s a membrane protein located in the lumen of the endoplasmic reticulum.
Therefore, glucose-6-phosphate is transported from the cytosol into the endoplasmic reticulum
for the final reaction step.
This task is performed by glucose-6-phosphate translocase.
In the endoplasmic reticulum, the last remaining phosphate group is cleaved from the molecule,
yielding glucose and free phosphate.
Again, the reaction doesn’t generate ATP.
For the energy balance of gluconeogenesis, a total of four molecules of ATP, two GTP,
and two reducing equivalents of NADH and H+ are required to produce one molecule of glucose.
If the physiologically produced glucose is broken down again later in glycolysis, only
two reducing equivalents of NADH and H+ and two ATP molecules can be recovered.
In this case, gluconeogenesis ultimately consumes two molecules each of ATP and GTP.
So, if we look at gluconeogenesis from an energy perspective, it’s a less efficient
metabolic process.
A metabolic disease associated with gluconeogenesis is glycogen storage disease type I, also known
as von Gierke disease, which belongs to the glycogenoses.
Type Ia is due to a defect of glucose-6-phosphatase, whereas type Ib concerns glucose-6-phosphate
translocase.
Both cases result in a defective conversion of glucose-6-phosphate into glucose.
Since glucose can only leave the cells in a non-phosphorylated form, glycogen storage
disease type I causes recurrent hypoglycemia.
In order for patients to maintain their blood sugar level without regularly raiding the
fridge and eating meals during the night, nasogastric tubes are used during this time.
These tubes provide patients with an adjusted dose of glucose.
Let’s summarize the most important aspects of gluconeogenesis that we’ve mentioned
so far:
The aim of gluconeogenesis is to supply glucose-dependent cells with energy from non-carbohydrate substrates
and to bridge periods of prolonged food deprivation.
In gluconeogenesis, one molecule of glucose is produced from two molecules of pyruvate
in 11 reaction steps.
The first step of gluconeogenesis occurs exclusively in the mitochondrion, the last step in the
endoplasmic reticulum, and all others in the cytosol.
Gluconeogenesis reactions are essentially the reverse reactions of glycolysis.
Exceptions are the reactions catalyzed by the irreversible key enzymes of glycolysis:
Pyruvate is converted to phosphoenolpyruvate by two enzymes specific to gluconeogenesis
via the intermediate oxaloacetate.
The reactions from fructose-1,6-bisphosphate to fructose-6-phosphate and glucose-6-phosphate
to glucose are also catalyzed by enzymes specific to gluconeogenesis.
For each molecule of glucose, 4 ATP, 2 GTP, and 2 NADH and H+ are used in gluconeogenesis.
Of these, only 2 ATP and 2 NADH and H+ can be recovered through renewed glycolysis.
Would you like to test your knowledge of gluconeogenesis before continuing with its regulation in the
next episode?
Check out the quiz on the next slide.