How can glycolysis be regulated?||Biochemistry:

Introduction:

The regulatory enzymes of the glycolytic pathway are phosphofructokinase, hexokinase,and pyruvate kinase .

⏹️ Role of Phosphofructokinase in the regulation of glycolysis:

The most important control step of glycolysis is the irreversible reaction catalyzed by phosphofructokinase .The enzyme is regulated in several ways :

Citrate:

Citrate, the first product of the citric acid cycle ,can inhibit the activity of phosphofructokinase.

An increased amount of citrate, indicates that there is already present an increased amount of citric acid cycle intermediates.Hence no additional breakdown of glucose via glycolysis is needed.

ATP/AMP:

PFK is allosterically inhibited by ATP but this inhibition is reversed by AMP .

This allows glycolysis to be responsive to the energy needs of the cell, speeding up when ATP is in short supply (and AMP is plentiful) so that more ATP can be made,and slowing down when sufficient ATP is already available.

Regulations of glycolysis

H+ions:

Hydrogen ions ,the other glycolytic end product,has an important role in the inhibition phosphofructokinase. Hydrogen ions are able to shut off glycolysis,the process responsible for decreasing pH.

Hydrogen ions can prevent the excessive formation of lactate under anaerobic conditions and therefore prevents medical condition known as acidosis.

Fructose 2,6-bisphosphate:

Fructose 2,6-bisphosphate is another important factor which can regulate the acitivity of PFK and therefore control the process of glycolysis in the liver .

Fructose 2, 6 bisphosphate is synthesized from fructose 6 phosphate by the enzyme phospho fructokinase called PFK2 , which is different from PFK .

Fructose 2,6-bisphosphate is hydrolyzed back to fructose 6 phosphate by fructose bisphosphatase 2. The activity of PFK2 and FBPase2 ,are catalyzed by the same polypeptide,hence this is known as a bi-functional enzyme.

Fructose 6-phosphate stimulates the synthesis of fructose 2,6 Bishopsgate and inhibits its hydrolysis.Fructose 2,6 bisphosphate in turn strongly activates PFK and hence stimulates glycolysis.

From the above explanation we can say that PFK is stimulated when the levels of fructose 6-phosphate is high . The activity of of PFK2 and FBPase2 are also controlled by covalent modification.

When the level of glucose present in the blood , falls ,then the hormone glucagon is released in the blood stream.

Which then triggers a cyclic AMP cascade that leads to the phosphorylation of the PFK2/FBPase2 polypeptide at a single serine residue.

This activates FBPase2 and inhibits PFK2,lowering the level of fructose 2,6-bisphosphate and hence decreasing the rate of glycolysis. The opposite case happen when the level of glucose in the blood rises.

In this case the phosphate group is removed from the PFK2/FBPase2 polypeptide by a phosphatase thus inhibiting FBPase2 and activating PFK2, raising the level of fructose 2,6-bisphosphate and hence increasing the rate of glycolysis.

Role of Hexokinase in the regulation of glycolysis:

The first step of glycolysis,that is the phosphorylation of glucose by ATP to form glucose 6 phosphate and ADP is catalyzed by the enzyme hexokinase. This is the first irreversible steps of glycolysis.

The activity of the enzyme hexokinase is inhibited by glucose 6 phosphate.

Thus when PFK is inhibited, fructose 6-phosphate builds up and so does glucose 6-phosphate,since these two metabolites are in equilibrium via phosphoglucoisomerase .

The hexokinase inhibition then reinforces the inhibition at the PFK step .

Role of Pyruvate kinase in the regulation of glycolysis:

Pyruvate kinase is another regulatory enzyme of glycolysis which catalyzes the third irreversible step in glycolysis. Fructose 1,6 bisphosphate helps in the activation of pyruvate kinase.

This enzyme is drastically inhibited by physiological concentrations of ATP ,so much, so that its potential activity is never fully realized under physiological conditions.

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