Biochemistry/Regulation of glycolysis and gluconeogenesis

Regulation of glycolysis and glyconeogenesis occurs on the enzymes of irreversible steps.

For glycolysis these enzymes are hexokinase, PFK-1 and pyruvate kinase.

Regulation is achieved by allosterically or by means of post-translational modification or via controling the level of mRNA. It is possible to observe combination of this methods.

It is well known that PFK-1 is the pacemaker of glycolysis. Because of that it is not wrong to start with 3rd enzyme of the glycolysis.

PFK-1
A surplus of ATP allosterically affects PFK-1. It behaves as a negative regulator of the enzyme, in high amounts. The answer to the question "how does this enzyme sense that ATP is abundant or found in low levels" is that this enzyme has two sites for ATP binding. When ATP is low, only one molecule of ATP per enzyme can be linked. While ATP is abundant, both of the places for ATP are occupied and the activity of the enzyme is dramatically lowered. The connection of only one molecule ATP per enzyme supports the action of the enzyme.

Opposite to the influences of a high level of ATP, AMP functions in a reverse way to recover the results of abundant ATP on PFK-1. The presence of plenty of ATP infers that the cell is satisfied with an energy source. Thus glucose is not required to be broken down. Moreover, the existence of a high level of AMP means that the cell needs energy. Therefore glycolysis should continue to flow in the direction of the pyruvate.

A surplus of citrates is another allosteric inhibitor of PFK-1, indicating an abundance of biosynthetic precursors.

As was earlier stated, alternative paths to control metabolism exist in addition to allosteric regulation. Low pH sourced from lactic acid fermentation prevents working of PFK-1 and leads acidosis, too.

Although PFK-1 is the most strictly regulated irreversible step, other rate-limiting steps of glycolysis are also regulated at some level.

Hexokinase
Hexokinase, even, does not need to "foreing" chemical so as to be inhibited. Its own product G6P is capable of preventing the functioning of hexokinase. In this condition, G6P signals energy source is enough.

When PFK-1 is deactivated, F6P cannot be converted to F16BP. Because G6P to F6P reaction is reversible, F6P which could not be converted to F16BP is converted to G6P. G6P accumulates and negatively influence the working of hexokinase. This pathway demonstrates inhibition of PFK-1 also means that canceling out of hexokinase, indirectly. This position of PFK-1 make it pacemaker of glycolysis.

In liver, hexokinase(IV) is controlled via sequestration into nucleus by the help of its regulatory protein.The regulatory protein is directed by glucose and F6P. F6P signals regulatory protein-hexokinase complex to go into nucles in order to stop glycolysis while glucose call this complex into cytoplasm so as to carry out first step of glycolysis.

Pyruvate Kinase
Pyruvate kinase, end and last irreversible step enzyme of glycolysis, is kept active by the help of F16BP while it is being inactivated via ATP.

At liver, L isozyme of pyruvate kinase regulated also by phosphorylation, according to availibility of energy source and other factors.