Energy metabolism Part 11 - How is gluconeogenesis regulated?
Generally speaking, glucose provides the body with energy right?
If glycolysis degrades the glucose initially absorbed with a meal, then we can agree with
this statement.
Here, the body gains a total of two molecules of ATP and two reducing equivalents of NADH
and H+ per glucose molecule.
However, if the degraded glucose was produced in the body, the statement is not entirely
correct: In gluconeogenesis, the body invests four molecules of ATP, two GTP, and two NADH
and H+.
If this expenditure is included in the energy balance for glycolysis, it becomes rapidly
clear that the breakdown of the glucose produced by the body isn’t an energy-efficient process.
Gluconeogenesis isn’t obviously carried out to counteract energy deficiency, like
glycolysis, but to compensate for glucose deficiency.
This is important, because some cells, such as those of the brain or erythrocytes, depend
on glucose as a source of energy.
The counteracting processes of glycolysis and gluconeogenesis need to be coordinated
carefully so that they don’t occur at the same time.
Otherwise, energy could be easily wasted.
Coordination is enabled by reciprocal regulatory processes.
Suitable starting points for regulation are enzymes that are specific to either glycolysis
or gluconeogenesis, that is, the respective key enzymes.
Details on glycolysis regulation can be found in part 3 of our energy metabolism course.
Now, here we’ll discuss the most important regulatory mechanisms of gluconeogenesis:
The first opportunity for specific regulation arises in the first reaction step of gluconeogenesis.
The responsible enzyme, pyruvate carboxylase, is inhibited by ADP in case of energy deficiency.
If there’s not enough energy available in the cell, glucose synthesis, which is energetically
demanding, wouldn’t be physiologically reasonable.
In contrast, acetyl-CoA stimulates pyruvate carboxylase.
In fact, this activation isn’t directly related to gluconeogenesis.
Do you remember what we said about the reaction in our last episode?
Well, the oxaloacetate produced by pyruvate carboxylase isn’t only used in gluconeogenesis
but also serves as a molecular carrier in the citric acid cycle.
Acetyl-CoA is the main substrate of the citric acid cycle and accumulates if there’s not
enough oxaloacetate.
So, the activation of pyruvate carboxylase by acetyl-CoA is intended to facilitate the
citric acid cycle rather than gluconeogenesis.
The second enzyme that regulates gluconeogenesis is phosphoenolpyruvate carboxykinase.
It catalyzes the second step of gluconeogenesis.
Phosphoenolpyruvate carboxykinase is again inhibited by excess ADP during energy deficiency.
While ADP inhibits the conversion of pyruvate to phosphoenolpyruvate in gluconeogenesis,
ATP inhibits the reverse reaction of phosphoenolpyruvate to pyruvate in glycolysis.
In this context, reciprocal regulation of glycolysis and gluconeogenesis means that
the corresponding sections of the metabolic pathways are inhibited by counterparts.
Another form of reciprocal regulation is found with the conversion of fructose-1,6-bisphosphate
and fructose-6-phosphate.
In gluconeogenesis, fructose-1,6-bisphosphatase is inhibited by AMP and fructose-2,6-bisphosphate,
while it’s activated by citrate.
The reverse reaction in glycolysis, which is catalyzed by phosphofructokinase 1, however,
is activated by AMP and fructose-2,6-bisphosphate but inhibited by citrate.
Here, reciprocal regulation means that the same regulators have different effects when
acting on enzymes with opposite functions.
Physiologically, AMP, like ADP, indicates lack of energy in the cell.
Fructose-2,6-bisphosphate, however, is mainly used for tissue-specific adaptation of metabolism
by the signaling molecule cAMP.
More information on tissue-specific adaptation can be found in the corresponding AMBOSS article.
Finally, citrate signals a sufficient cellular energy supply and, therefore, has the opposite
effect of AMP.
OK.
Before we finish, let’s summarize the most important points:
Gluconeogenesis and glycolysis are coordinated so that one process is stimulated while the
other is inhibited.
This relationship is also called reciprocal regulation.
Gluconeogenesis is regulated by its three key enzymes pyruvate carboxylase, phosphoenolpyruvate
carboxykinase, and fructose-1,6-bisphosphatase.
Pyruvate carboxylase is inhibited by ADP and stimulated by acetyl-CoA; phosphoenolpyruvate
carboxykinase is also inhibited by ADP; fructose 1,6-bisphosphatase is instead inhibited by
AMP and by fructose 2,6-bisphosphate, while activated by citrate.
In the present and previous episode, we introduced you to the most important aspects of gluconeogenesis.
How about now testing your newfound knowledge in a quiz?
Stay put for the next slide.