Pyruvate kinase
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
.
This process also requires a Magnesium 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 final product of aerobic glycolysis. However, in anaerobic glycolysis, lactate dehydrogenase
will utilize the NADH produced by glyceraldehyde phosphate dehydrogenase to reduce pyruvate to lactate. In humans, there are two pyruvate kinase isozymes: type M (muscle, SwissProt P14618) and type L,R (liver and erythrocyte, SwissProt P30613). The isozymes differ in primary structure and regulation.
change, one of three in glycolysis. All three such steps regulate the overall activity of the pathway, and are, in general, irreversible under wild-type conditions.
Pyruvate kinase activity is regulated by:
Liver pyruvate kinase is also regulated indirectly by epinephrine
and glucagon
, through protein kinase A. This protein kinase phosphorylates liver pyruvate kinase to deactivate it. Muscle pyruvate kinase is not inhibited by epinephrine activation of protein kinase A. Glucagon signals fasting (no glucose available). Thus, glycolysis
is inhibited in the liver but unaffected in muscle when fasting. 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 that 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.
. 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
.
, 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.
and has been transferred to a number of anaerobic eukaryote
groups (for example, Streblomastix
, Giardia
, Entamoeba
, and Trichomonas
), it seems via horizontal gene transfer
on two or more occasions. In some cases, the same organism will have both Pyruvate kinase and PPDK.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
involved in glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate
Phosphoenolpyruvate
Phosphoenolpyruvic acid , or phosphoenolpyruvate as the anion, is an important chemical compound in biochemistry. It has the high-energy phosphate bond found in living organisms, and is involved in glycolysis and gluconeogenesis...
(PEP) to ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
, yielding one molecule of pyruvate and one molecule of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
.
Reaction
The reaction with pyruvate kinase:This step is the final one in the glycolytic pathway, which produces pyruvate molecules, the final product of aerobic glycolysis. However, in anaerobic glycolysis, lactate dehydrogenase
Lactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
will utilize the NADH produced by glyceraldehyde phosphate dehydrogenase to reduce pyruvate to lactate. In humans, there are two pyruvate kinase isozymes: type M (muscle, SwissProt P14618) and type L,R (liver and erythrocyte, SwissProt P30613). The isozymes differ in primary structure and regulation.
Regulation
This reaction has a large negative free energyThermodynamic free energy
The thermodynamic free energy is the amount of work that a thermodynamic system can perform. The concept is useful in the thermodynamics of chemical or thermal processes in engineering and science. The free energy is the internal energy of a system less the amount of energy that cannot be used to...
change, one of three in glycolysis. All three such steps regulate the overall activity of the pathway, and are, in general, irreversible under wild-type conditions.
Pyruvate kinase activity is regulated by:
- Its own substrateSubstrate (biochemistry)In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
PEP and fructose 1,6-bisphosphateFructose 1,6-bisphosphateFructose 1,6-bisphosphate is fructose sugar phosphorylated on carbons 1 and 6 . The β-D-form of this compound is very common in cells...
, an intermediate in glycolysis, both of which 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 whether citrateCitrateA citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
plays a role in negative allosteric inhibition, however it is believed that acetyl-CoA does. - AlanineAlanineAlanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
, a negative allosteric modulator
Liver pyruvate kinase is also regulated indirectly by epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
and glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
, through protein kinase A. This protein kinase phosphorylates liver pyruvate kinase to deactivate it. Muscle pyruvate kinase is not inhibited by epinephrine activation of protein kinase A. Glucagon signals fasting (no glucose available). Thus, glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
is inhibited in the liver but unaffected in muscle when fasting. An increase in blood sugar leads to secretion of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, 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 that catalyze the reverse reaction (pyruvate carboxylase
Pyruvate carboxylase
Pyruvate carboxylase is an enzyme of the ligase class that catalyzes the irreversible carboxylation of pyruvate to form oxaloacetate .It is an important anaplerotic reaction that creates oxaloacetate from pyruvate...
and phosphoenolpyruvate carboxykinase
Phosphoenolpyruvate carboxykinase
Phosphoenolpyruvate carboxykinase is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.It is found in two forms, cytosolic and mitochondrial....
), preventing a futile cycle
Futile cycle
A futile cycle, also known as a substrate cycle, occurs when two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat...
.
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 deficiencyPyruvate kinase deficiency
Pyruvate kinase deficiency, also called erythrocyte pyruvate kinase deficiency, is an inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells and causes them to deform into echinocytes on peripheral blood smears.Both autosomal dominant and recessive...
. 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
Fermentation (biochemistry)
Fermentation is the process of extracting energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. In contrast, respiration is where electrons are donated to an exogenous electron acceptor, such as oxygen,...
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
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
. Therefore, pyruvate kinase deficiency can cause hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
.
Role in gluconeogenesis
Pyruvate kinase also serves as a regulatory enzyme for gluconeogenesisGluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
, a biochemical pathway in which the liver generates glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
from pyruvate and other substrates. When pyruvate kinase is inhibited by phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
(which occurs in the fasting state, via glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
), 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.
Alternatives
A reversible enzyme with a similar function, Pyruvate phosphate dikinase (PPDK), is found in some bacteriaBacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and has been transferred to a number of anaerobic eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
groups (for example, Streblomastix
Streblomastix
A symbiotic eukaryote that lives in the stomach of termites, and other insects, Streblomastix is a protist that helps to digest wood along with other protists....
, Giardia
Giardia
Giardia is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada in the supergroup "Excavata" that colonise and reproduce in the small intestines of several vertebrates, causing giardiasis, commonly known as Beaver fever...
, Entamoeba
Entamoeba
Entamoeba is a genus of Amoebozoa found as internal parasites or commensals of animals.In 1875, Fedor Lösch described the first proven case of amoebic dysentery in St Petersburg, Russia. He referred to the amoeba he observed microscopically as 'Amoeba coli'; however it is not clear whether he was...
, and Trichomonas
Trichomonas
Trichomonas is a genus of anaerobic protists that are parasites of vertebrates. They are included with the parabasalids.Species of Trichomonas include:*Trichomonas vaginalis, an organism generally living inside the vagina of humans...
), it seems via horizontal gene transfer
Horizontal gene transfer
Horizontal gene transfer , also lateral gene transfer , is any process in which an organism incorporates genetic material from another organism without being the offspring of that organism...
on two or more occasions. In some cases, the same organism will have both Pyruvate kinase and PPDK.