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Regulation of the Glycolytic Pathway
There are total ten enzymes in the glycolytic pathway but not all the enzymes are involved in the regulation, but only three of them are important for the point of regulation of glycolytic pathway. These enzymes are mostly regulated by allosteric regulation but also regulated hormonal and to some extent by covalent modifications. Because these enzymes are involved in an irreversible reaction they are the targets of regulation. These are as follows. 1: Hexokinase/Glucokinase, 2: Phosphofructokinase (PFK), 3: Pyruvate Kinase
1. Regulation of Hexokinase:
Hexokinase phosphorylates glucose in most animals, plants and microbes. This enzyme requires Mg++ ion because real substrate of this enzyme is Mg-ATP complex. Hexokinase catalyzes the first irreversible reaction of the glycolytic pathway and is inhibited by the glucose-6-phosphate i.e. when the product glucose-6-phosphate is accumulated, it inhibits the enzyme catalyzes the production of it. Glucokinase found in the liver is an isoenzyme of hexokinase which is not inhibited by glucose-6-phosphate and is involved in glucose-1-phosphate formation for glycogen synthesis. Therefore, Hexokinase is the first target of regulation of glycolytic pathway.
2. Regulation of Phosphofructokinase-1 (PFK-1):
This enzyme catalyzes the irreversible conversion of fructose 6-phosphate into fructose-1, 6-bisphosphate. Formation of the fructose-1,6-bisphosphate is a committing step, because once it is formed, it is committed to go through the glycolytic pathway, leading to the pyruvate.
Phosphofructokinase-1 is a homotetramer with two conformational states R (active or relaxed state) and T (inactive or tensed state). These conformers are in equilibrium. PFK-1 can be reversibly dissociated into its dimmers and is regulated by allosteric activators/inhibitors. ATP is a substrate of this enzyme which can allosterically inhibit the enzyme activity.
However, this allosteric inhibition can be reversed by AMP, ADP, or Fructose-2,6-bisphosphate. PFK-1 is also inhibited by low pH and by citrate. This is a signal that indicates the abundance of intermediates inside the cell.
Fructose-2,6-bisphosphate converts T-state of PFK-1 to the R-state of PFK-1. It activates the enzyme by increasing affinity for the fructose-6-phosphate because R-state has more affinity for fructose 6-phosphate than T-state. According to concerted model activators preferentially bind to R state and inhibitors preferentially bind to the T state.
Phosphofructokinase 2 and Fructose Bisphosphatase-2
The Phosphofructokinase-2(PFK 2) and the Fructose Bisphosphatase-2(FBPase 2) activities are exhibited by a single polypeptide. This polypeptide chain contains three domains of which two domains are catalytic and one is regulatory. Fructose-6-phosphate stimulates the formation of fructose-2,6- bisphosphate by activating PFK-2 and inhibits the formation of itself by inhibiting fructose bisphosphatase-2 (FBPase 2).
2.1 Hormonal Regulation of PFK:
There are two major hormones; glucagon and epinephrine (adrenalin) that regulate the activity of phosphofructokinase 1. Glucagon maintains blood glucose level. This process is called as a homeostasis while epinephrine is released in response to fight/flight (in danger condition). When blood glucose is decreased, glucagon is released which initiates the cAMP cascade.
This leads to the phosphorylation of bifunctional enzyme activating Fructosebisphosphatase-2 and inhibits Phosphofructokinase-2. The ultimate is decreased in fructose-2,6-bisphosphate concentration. The decreased concentration of fructose 2,6 bisphosphate causes the formation of fructose-6-phosphate thus increasing the blood glucose level. Thus, Phosphofructokinase-1 and Fructose Bisphoaphatase-2 also play an important role in the regulation of glycolytic pathway.
3. Regulation of Pyruvate Kinase:
Pyruvate Kinase controls the outflow product of glycolysis. It produces ATP and pyruvate. It is activated by fructose-1,6-bisphossphate and allosterically inhibited by ATP and alanine. These are the signals that indicate the presence of a plenty of energy. There are two types of pyruvate kinases; one is L-form found in the liver and the other is M-form found in the muscles and brain.
The pyruvate kinase is controlled by reversible phosphorylation. It can also be regulated hormones. When blood glucose level falls then glucagon triggers the initiation of cAMP signaling cascade which phosphorylates the pyruvate kinase increasing the enzyme activity. While blood glucose level rises vasopressin signals to dephosphorylation of pyruvate kinase thus inhibiting the enzyme activity. Thus, blood glucose level is maintained
In conclusion, all these enzymes are extremely important to maintain the influx and outflux and are the points of regulation of glycolytic pathway.