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Pyruvate kinase
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Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate and one molecule of ATP.
reaction with pyruvate kinase:
This process also requires a manganese ion. The enzyme is a transferase under the international classification of enzymes.
This step is the final one in the glycolytic pathway, which produces pyruvate molecules.
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Encyclopedia
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate and one molecule of ATP.
Reaction
The reaction with pyruvate kinase:
This process also requires a manganese ion. The enzyme is a transferase under the international classification of enzymes.
This step is the final one in the glycolytic pathway, which produces pyruvate molecules. The pyruvate may next be used to regenerate NAD+ via fermentation, or can be converted (as acetyl CoA) to ATP. In humans, there are two isozymes: type M (muscle, SwissProt P14618) and type L,R (liver and erythrocyte, SwissProt P30613). The isozymes differ in primary sequence and regulation.
Regulation
This reaction has a large negative free energy change, one of three in glycolysis. All three such steps regulate the overall activity of the pathway, and are generally irreversible under physiological conditions.
Pyruvate kinase activity is regulated by:
- Its own substrate PEP and fructose 1,6-bisphosphate, an intermediate in glycolysis; which both enhance enzymatic activity. Thus, glycolysis is driven to operate faster when more substrate is present.
- ATP is a negative allosteric inhibitor. This accounts for parallel regulation with PFK 1.
- It is not known if citrate plays a role in negative allosteric inhibition, however it is believed acetyl-CoA does.
- Alanine, a negative allosteric modulator
Liver pyruvate kinase is also regulated indirectly by epinephrine and glucagon, through protein kinase A. This protein kinase phosphorylates liver pyruvate kinase to inactivate it. Muscle pyruvate kinase is not inhibited by epinephrine activation of protein kinase A. Glucagon signals fasting (no glucose available). An increase in blood sugar leads to secretion of insulin, which activates phosphoprotein phosphatase I, leading to dephosphorylation and activation of pyruvate kinase. These controls prevent pyruvate kinase from being active at the same time as the enzymes which catalyze the reverse reaction (pyruvate carboxylase and phosphoenolpyruvate carboxykinase), preventing a futile cycle.
In fact, to say that the forward reaction and reverse reaction are not both active simultaneously may not be entirely accurate. Futile cycles, also known as substrate cycles, are known to fine-tune flux through metabolic pathways.
Deficiency
Genetic defects of this enzyme cause the disease known as pyruvate kinase deficiency. In this condition, a lack of pyruvate kinase slows down the process of glycolysis. This effect is especially devastating in cells that lack mitochondria, because these cells must use anaerobic glycolysis as their sole source of energy because the TCA cycle is not available.
One example is red blood cells, which in a state of pyruvate kinase deficiency rapidly become deficient in ATP and can undergo hemolysis. Therefore, pyruvate kinase deficiency can cause hemolytic anemia.
Role in gluconeogenesis
Pyruvate kinase also serves as a regulatory enzyme for gluconeogenesis, a biochemical pathway in which the liver generates glucose from pyruvate and other substrates. When pyruvate kinase is inhibited by phosphorylation (which occurs in the fasting state, via glucagon), phosphoenolpyruvate is prevented from being converted to pyruvate. Instead, it is converted to glucose in a series of gluconeogenesis reactions that are mostly (but not exactly) the reverse sequence of glycolysis.
The glucose thus produced is expelled from the liver, providing energy for vital tissues in the fasting state.
See also
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