Glycolysis is series of enzyme catalyzed reaction occurring in living cells which converts Glucose into Pyruvate with the release of energy.
The flux through glycolytic pathway must be adjusted in response to conditions both inside and outside the cell. It produces short but high bursts of energy.
The rate of conversion of glucose into pyruvate is regulated to meet two major cellular needs:
- Production of ATP, generated by the degradation of glucose.
- Provision of building blocks for synthetic reactions, such as the formation of fatty acids.
Enzymes catalyzing the irreversible reactions in glycolytic pathway regulate glycolysis, namely hexokinase (glucokinase), phosphofructokinase and pyruvate kinase.
Hexokinase is inhibited by glucose 6-phosphate. This enzyme prevents accumulation of glucose 6-phosphate due to product inhibition. Glucokinase, which specifically phosphorylates glucose, is an inducible enzyme. Substrate glucose, probably through the involvement of insulin, induces glucokinase.
Phosphofructo kinase (PFK) is most important/ key regulatory enzyme in glycolysis which
catalyses rate limiting committed step. PFK is an allosteric enzyme regulated by allosteric effectors. ATP, citrate and H+ ions (low pH) are the most important allosteric inhibitors, whereas fructose 2,6-bisphosphate, ADP, AMP and Pi are the allosteric activators.
Pyruvate kinase is inhibited by ATP, Acetyl co-A while activated by Fructose 1, 6-bisphosphate. Pyruvate kinase is active in dephosphorylated state and inactive in phosphorylated state. CAMP-dependent protein kinase inactivates it by phosphorylation.
The reactions which are regulatory steps in glycolysis are:
- Formation of glucose-6-phosphate from glucose (Hexokinase).
- Fructose-6-phosphate to Fructose 1,6- bisphosphate (Phosphofructose kinase).
- Formation of pyruvate from phosphoenol pyruvate (Pyruvate kinase).
Mechanism of Regulation
Glycolysis can be regulated by three different types of mechanisms:
- Changes in the rate of enzyme synthesis, Induction/ repression.
- Covalent modification by reversible phosphorylation.
- Allosteric modification.
Induction and repression of key enzymes: It is a slow process which takes several hours to come into action.
- Glucose: When there is increased substrate, i.e. glucose, enzymes involved in utilization of
glucose are activated. On other hand, enzymes responsible for producing glucose i.e. gluconeogenesis are inhibited. Glucose also increases the activity of the key enzymes glucokinase, phosphofructokinase-1 and pyruvate kinase.
- Insulin: Secretion of insulin on response to blood glucose concentration enhances synthesis of the key enzymes responsible for glycolysis. On other hand, it antagonizes effects of glucocorticoids and glucagon-stimulated cAMP in stimulating the key enzymes responsible for gluconeogenesis.
Covalent modification by reversible phosphorylation: Hormones like epinephrine and glucagon which increase cAMP level activate cAMP-dependent protein kinase which can phosphorylate and inactivate the key enzyme pyruvate kinase and thus, inhibit glycolysis. It is a rapid process and occurs quickly.
Allosteric modification: Phosphofructokinase-1 is the key regulatory enzyme and is subject to feedback control. It is inhibited by citrate and by ATP while activated by AMP.
AMP acts as the indicator of energy status of the cell. When ATP is used in energy requiring processes resulting in formation of ADP, concentration of AMP increases.
Normally, ATP concentration may be fifty times that of AMP concentration at equilibrium, a small decrease in ATP concentration will cause a several fold rise in AMP concentration. Thus a large change in AMP concentration acts as metabolic amplifier of a small change in ATP concentration.
This mechanism allows activity of the enzyme phosphofructokinase-1 to be highly sensitive to even small changes of energy status of the cell and hence it controls the amount of glucose that should undergo glycolysis prior to its entry as acetyl-CoA in TCA cycle.
In hypoxia, concentration of ATP in the cells decreases and there is increase in concentration of
AMP thus, glycolysis should increase in absence of O2.
High concentrations of citrate indicate a plentiful supply of intermediates for energy production; therefore, high activity of the glycolytic pathway is inhibited by it.
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