Phosphoenolpyruvate carboxykinase
Encyclopedia
Phosphoenolpyruvate carboxykinase (PEPCK) 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, cytosol
ic and mitochondrial.
can use the glycolysis
enzymes in the opposite direction, the pyruvate kinase
enzyme is irreversible. The enzymes pyruvate carboxylase
and phosphoenolpyruvate carboxykinase provide an alternate path to effectively reverse the actions of pyruvate kinase.
occurs in many species, and the amino acid sequence of PEPCK is distinct for each species.
For example, its structure and its specificity differ in humans, Escherichia coli (E. coli), and the parasiteTrypanosoma cruzi
.
, the process by which cells synthesize glucose
from metabolic precursors. The blood glucose level is maintained within well-defined limits in part due to precise regulation of PEPCK gene expression. To emphasize the importance of PEPCK in glucose homeostasis
, over expression of this enzyme in mice results in symptoms of type II diabetes mellitus
, by far the most common form of diabetes in humans. Due to the importance of blood glucose homeostasis, a number of hormones regulate a set of genes
(including PEPCK) in the liver
that modulate the rate of glucose synthesis.
PEPCK is controlled by two different hormonal mechanisms. PEPCK activity is increased upon the secretion of both cortisol from the adrenal cortex and glucagon from the alpha cells of the pancreas. Glucagon indirectly elevates the expression of PEPCK by increasing the levels of cAMP (via activation of adenylyl cyclase) in the liver which consequently phosphorylates the S133 on a beta sheet in the CREB protein. CREB then binds upstream of the PEPCK gene at CRE (cAMP response element) and induces PEPCK transcription. Cortisol on the other hand, when released by the adrenal cortex, passes through the lipid membrane of liver cells (due to its hydrophobic nature it can pass directly through cell membranes) and then binds to a Glucocorticoid Receptor (GR). This receptor dimerizes and the cortisol/GR complex passes into the nucleus where it then binds to the Glucocorticoid Response Element (GRE) region in a similar manner to CREB and produces similar results (synthesis of more PEPCK).
Together, Cortisol and Glucagon can have huge synergistic results. Activating the PEPCK gene to levels that neither cortisol or glucagon could reach on their own.It is most abundant in the liver, kidney, and adipose tissue.
Researchers at Case Western Reserve University have discovered that overexpression of cytosolic PEPCK in skeletal muscle of mice causes them to be more active, more aggressive, and have longer lives than normal mice; see metabolic supermice
.
, carbon dioxide
is first fixed by combination with phosphoenolpyruvate
to form oxaloacetate in the mesophyll
. In PEPCK-type C4 plants the oxaloacetate is then converted to aspartate, which travels to the bundle sheath. In the bundle sheath cells
, aspartate is converted back to oxaloacetate. PEPCK decarboxylates the bundle sheath oxaloacetate, releasing carbon dioxide
, which is then fixed by the enzyme Rubisco
.
PEPCK acts in plants that undergo C4 carbon fixation
, where its action has been localized to the cytosol
, in contrast to mammals, where it has been found that PEPCK works in mitochondria.
Although it is found in many different parts of plants, it has been seen only in specific cell types, including the areas of the phloem
.
It has also been discovered that, in cucumber (Cucumis sativus L.), PEPCK levels are increased by multiple effects that are known to decrease the cellular pH of plants, although these effects are specific to the part of the plant.
PEPCK levels rose in roots and stems when the plants were watered with ammonium chloride
at a low pH (but not at high pH
), or with butyric acid
. However, PEPCK levels did not increase in leaves under these conditions.
In leaves, 5% CO2 content in the atmosphere leads to higher PEPCK abundance.
.
, the process whereby glucose is synthesized. The enzyme has therefore been thought to be essential in glucose homeostasis, as evidenced by laboratory mice that contracted diabetes mellitus type 2
as a result of the overexpression of PEPCK.
A recent study suggests that the role that PEPCK plays in gluconeogenesis may be mediated by the citric acid cycle
, the activity of which was found to be directly related to PEPCK abundance.
PEPCK levels alone were not found to be highly correlated with gluconeogenesis in the mouse liver, as previous studies have suggested. Therefore, the role of PEPCK in gluconeogenesis may be more complex and involve more factors than was previously believed.
PEPCK of Mycobacterium tuberculosis
has been shown to trigger the immune system in mice by increasing cytokine
activity.
As a result, it has been found that PEPCK may be an appropriate ingredient in the development of an effective subunit vaccination for tuberculosis
.
X-ray structures of PEPCK provide insight into the structure and the mechanism of PEPCK enzymatic activity. The mitochondrial isoform of chicken liver PEPCK complexed with Mn2+, Mn2+-phosphoenolpyruvate
(PEP), and Mn2+-GDP provides information about its structure and how this enzyme catalyzes reactions.
Delbaere et al. (2004) resolved PEPCK in E. coli and found the active site
sitting between a C-terminal domain and an N-terminal domain. The active site was observed to be closed upon rotation of these domains.
Phosphoryl groups are transferred during PEPCK action, which is likely facilitated by the eclipsed conformation of the phosphoryl groups when ATP is bound to PEPCK.
Since the eclipsed formation is one that is high in energy, phosphoryl group transfer has a decreased energy of activation, meaning that the groups will transfer more readily. This transfer likely happens via a mechanism similar to SN2 displacement.
and carbon dioxide
.
As PEPCK acts at the junction between glycolysis
and the Krebs cycle, it causes decarboxylation
of a C4 molecule, creating a C3 molecule. As the first committed step in gluconeogenesis, PEPCK decarboxylates, and phosphorylates oxaloacetate (OAA) for its conversion to PEP, when GTP is present. As a phosphate is transferred, the reaction results in a GDP molecule. It is interesting to note that, when pyruvate kinase
- the enzyme that normally catalyzes the reaction that converts PEP to pyruvate - is knocked out in mutants of Bacillus subtilis
, PEPCK participates in one of the replacement anaplerotic reactions
, working in the reverse direction of its normal function, converting PEP to OAA. Although this reaction is possible, the kinetics are so unfavorable that the mutants grow at a very slow pace or do not grow at all.
In fermentation
, PEPCK catalyzes the reaction of PEP and carbon dioxide to OAA and ADP is therefore converted to ATP with the addition of a phosphate group.
, glucocorticoids, retinoic acid
, and adenosine 3’,5’-monophosphate (cAMP
), while it is inhibited by insulin
. Of these factors, insulin, a hormone that is deficient in the case of diabetes, is considered dominant, as it inhibits the transcription of many of the stimulatory elements. PEPCK activity is also inhibited by hydrazine sulfate
, and the inhibition therefore decreases the rate of gluconeogenesis.
In prolonged acidosis
, PEPCK is upregulated in renal proximal tubule brush border cells, in order to secrete more NH3
and thus to produce more HCO3-
.
The GTP-specific activity of PEPCK is highest when Mn2+ and Mg2+ are available. In addition, hyper-reactive cysteine
(C307) is involved in the binding of Mn2+ to the active site.
4.1.1. There are three main types, distinguished by the source of the energy to drive the reaction:
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...
in the lyase
Lyase
In biochemistry, a lyase is an enzyme that catalyzes the breaking of various chemical bonds by means other than hydrolysis and oxidation, often forming a new double bond or a new ring structure...
family used in the metabolic pathway of gluconeogenesis
Gluconeogenesis
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....
. It converts oxaloacetate into 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...
and carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
.
It is found in two forms, cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
ic and mitochondrial.
Reversibility
Whereas most reactions of 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....
can use the glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
enzymes in the opposite direction, the pyruvate kinase
Pyruvate kinase
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding one molecule of pyruvate and one molecule of ATP.-Reaction:The reaction with pyruvate kinase:...
enzyme is irreversible. The enzymes 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 provide an alternate path to effectively reverse the actions of pyruvate kinase.
PEPCK in different species
PEPCK gene transcription (genetics)Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
occurs in many species, and the amino acid sequence of PEPCK is distinct for each species.
For example, its structure and its specificity differ in humans, Escherichia coli (E. coli), and the parasiteTrypanosoma cruzi
Trypanosoma cruzi
Trypanosoma cruzi is a species of parasitic euglenoid trypanosomes. This species causes the trypanosomiasis diseases in humans and animals in America...
.
Animals
In animals, this is a rate-controlling step of 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....
, the process by which cells synthesize 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 metabolic precursors. The blood glucose level is maintained within well-defined limits in part due to precise regulation of PEPCK gene expression. To emphasize the importance of PEPCK in glucose homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
, over expression of this enzyme in mice results in symptoms of type II diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, by far the most common form of diabetes in humans. Due to the importance of blood glucose homeostasis, a number of hormones regulate a set of genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
(including PEPCK) in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
that modulate the rate of glucose synthesis.
PEPCK is controlled by two different hormonal mechanisms. PEPCK activity is increased upon the secretion of both cortisol from the adrenal cortex and glucagon from the alpha cells of the pancreas. Glucagon indirectly elevates the expression of PEPCK by increasing the levels of cAMP (via activation of adenylyl cyclase) in the liver which consequently phosphorylates the S133 on a beta sheet in the CREB protein. CREB then binds upstream of the PEPCK gene at CRE (cAMP response element) and induces PEPCK transcription. Cortisol on the other hand, when released by the adrenal cortex, passes through the lipid membrane of liver cells (due to its hydrophobic nature it can pass directly through cell membranes) and then binds to a Glucocorticoid Receptor (GR). This receptor dimerizes and the cortisol/GR complex passes into the nucleus where it then binds to the Glucocorticoid Response Element (GRE) region in a similar manner to CREB and produces similar results (synthesis of more PEPCK).
Together, Cortisol and Glucagon can have huge synergistic results. Activating the PEPCK gene to levels that neither cortisol or glucagon could reach on their own.It is most abundant in the liver, kidney, and adipose tissue.
Researchers at Case Western Reserve University have discovered that overexpression of cytosolic PEPCK in skeletal muscle of mice causes them to be more active, more aggressive, and have longer lives than normal mice; see metabolic supermice
Metabolic supermice
Metabolic supermice are mice which as a result of genetic modification have up to 100 times the concentration of the PEPCK-C enzyme in their muscles, compared to ordinary mice....
.
Plants
In plant C4 carbon fixationC4 carbon fixation
C4 carbon fixation is one of three biochemical mechanisms, along with and CAM photosynthesis, used in carbon fixation. It is named for the 4-carbon molecule present in the first product of carbon fixation in these plants, in contrast to the 3-carbon molecule products in plants. fixation is an...
, carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
is first fixed by combination with 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...
to form oxaloacetate in the mesophyll
Mesophyll
Mesophyll can refer to:* Mesophyll tissue, in plant anatomy, photosynthetic parenchyma cells that lie between the upper and lower epidermis layers of a leaf...
. In PEPCK-type C4 plants the oxaloacetate is then converted to aspartate, which travels to the bundle sheath. In the bundle sheath cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, aspartate is converted back to oxaloacetate. PEPCK decarboxylates the bundle sheath oxaloacetate, releasing carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
, which is then fixed by the enzyme Rubisco
RuBisCO
Ribulose-1,5-bisphosphate carboxylase oxygenase, commonly known by the shorter name RuBisCO, is an enzyme involved in the first major step of carbon fixation, a process by which atmospheric carbon dioxide is converted by plants to energy-rich molecules such as glucose. RuBisCo is an abbreviation...
.
PEPCK acts in plants that undergo C4 carbon fixation
C4 carbon fixation
C4 carbon fixation is one of three biochemical mechanisms, along with and CAM photosynthesis, used in carbon fixation. It is named for the 4-carbon molecule present in the first product of carbon fixation in these plants, in contrast to the 3-carbon molecule products in plants. fixation is an...
, where its action has been localized to the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, in contrast to mammals, where it has been found that PEPCK works in mitochondria.
Although it is found in many different parts of plants, it has been seen only in specific cell types, including the areas of the phloem
Phloem
In vascular plants, phloem is the living tissue that carries organic nutrients , in particular, glucose, a sugar, to all parts of the plant where needed. In trees, the phloem is the innermost layer of the bark, hence the name, derived from the Greek word "bark"...
.
It has also been discovered that, in cucumber (Cucumis sativus L.), PEPCK levels are increased by multiple effects that are known to decrease the cellular pH of plants, although these effects are specific to the part of the plant.
PEPCK levels rose in roots and stems when the plants were watered with ammonium chloride
Ammonium chloride
Ammonium chloride NH4Cl is an inorganic compound with the formula NH4Cl. It is a white crystalline salt that is highly soluble in water. Solutions of ammonium chloride are mildly acidic. Sal ammoniac is a name of natural, mineralogical form of ammonium chloride...
at a low pH (but not at high pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
), or with butyric acid
Butyric acid
Butyric acid , also known under the systematic name butanoic acid, is a carboxylic acid with the structural formula CH3CH2CH2-COOH. Salts and esters of butyric acid are known as butyrates or butanoates...
. However, PEPCK levels did not increase in leaves under these conditions.
In leaves, 5% CO2 content in the atmosphere leads to higher PEPCK abundance.
Bacteria
In an effort to explore the role of PEPCK, researchers caused the overexpression of PEPCK in E. coli bacteria via recombinant DNARecombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
.
Function in gluconeogenesis
It has been shown that PEPCK catalyzes the rate-controlling step of 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....
, the process whereby glucose is synthesized. The enzyme has therefore been thought to be essential in glucose homeostasis, as evidenced by laboratory mice that contracted diabetes mellitus type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
as a result of the overexpression of PEPCK.
A recent study suggests that the role that PEPCK plays in gluconeogenesis may be mediated by the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
, the activity of which was found to be directly related to PEPCK abundance.
PEPCK levels alone were not found to be highly correlated with gluconeogenesis in the mouse liver, as previous studies have suggested. Therefore, the role of PEPCK in gluconeogenesis may be more complex and involve more factors than was previously believed.
PEPCK of Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
has been shown to trigger the immune system in mice by increasing cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
activity.
As a result, it has been found that PEPCK may be an appropriate ingredient in the development of an effective subunit vaccination for tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
.
Structure
In humans there are two isoforms of PEPCK; a cytosolic form (SwissProt P35558) and a mitochondrial isoform (SwissProt Q16822) which have 63.4% sequence identity. The cytosolic form is important in gluconeogenesis. However, there is a known transport mechanism to move PEP from the mitochondria to the cytosol, using specific membrane transport proteins.X-ray structures of PEPCK provide insight into the structure and the mechanism of PEPCK enzymatic activity. The mitochondrial isoform of chicken liver PEPCK complexed with Mn2+, Mn2+-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), and Mn2+-GDP provides information about its structure and how this enzyme catalyzes reactions.
Delbaere et al. (2004) resolved PEPCK in E. coli and found the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
sitting between a C-terminal domain and an N-terminal domain. The active site was observed to be closed upon rotation of these domains.
Phosphoryl groups are transferred during PEPCK action, which is likely facilitated by the eclipsed conformation of the phosphoryl groups when ATP is bound to PEPCK.
Since the eclipsed formation is one that is high in energy, phosphoryl group transfer has a decreased energy of activation, meaning that the groups will transfer more readily. This transfer likely happens via a mechanism similar to SN2 displacement.
Reaction Pathway
PEPCase converts oxaloacetate into phosphoenolpyruvatePhosphoenolpyruvate
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...
and carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
.
As PEPCK acts at the junction between glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
and the Krebs cycle, it causes decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
of a C4 molecule, creating a C3 molecule. As the first committed step in gluconeogenesis, PEPCK decarboxylates, and phosphorylates oxaloacetate (OAA) for its conversion to PEP, when GTP is present. As a phosphate is transferred, the reaction results in a GDP molecule. It is interesting to note that, when pyruvate kinase
Pyruvate kinase
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding one molecule of pyruvate and one molecule of ATP.-Reaction:The reaction with pyruvate kinase:...
- the enzyme that normally catalyzes the reaction that converts PEP to pyruvate - is knocked out in mutants of Bacillus subtilis
Bacillus subtilis
Bacillus subtilis, known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium commonly found in soil. A member of the genus Bacillus, B. subtilis is rod-shaped, and has the ability to form a tough, protective endospore, allowing the organism to tolerate...
, PEPCK participates in one of the replacement anaplerotic reactions
Anaplerotic reactions
Anaplerotic reactions are those that form intermediates of a metabolic pathway. Examples of such are found in the Tricarboxylic acid Cycle...
, working in the reverse direction of its normal function, converting PEP to OAA. Although this reaction is possible, the kinetics are so unfavorable that the mutants grow at a very slow pace or do not grow at all.
In fermentation
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,...
, PEPCK catalyzes the reaction of PEP and carbon dioxide to OAA and ADP is therefore converted to ATP with the addition of a phosphate group.
In humans
PEPCK is enhanced, both in terms of its production and activation, by many factors. Transcription of the PEPCK gene is stimulated by glucagonGlucagon
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...
, glucocorticoids, retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
, and adenosine 3’,5’-monophosphate (cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
), while it is inhibited by 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....
. Of these factors, insulin, a hormone that is deficient in the case of diabetes, is considered dominant, as it inhibits the transcription of many of the stimulatory elements. PEPCK activity is also inhibited by hydrazine sulfate
Hydrazine sulfate
Hydrazine sulfate is the salt of hydrazine and sulfuric acid. Known by the trade name Sehydrin, it is a chemical compound that has been used as an alternative medical treatment for the loss of appetite and weight loss which is often associated with cancer...
, and the inhibition therefore decreases the rate of gluconeogenesis.
In prolonged acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
, PEPCK is upregulated in renal proximal tubule brush border cells, in order to secrete more NH3
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
and thus to produce more HCO3-
Bicarbonate
In inorganic chemistry, bicarbonate is an intermediate form in the deprotonation of carbonic acid...
.
The GTP-specific activity of PEPCK is highest when Mn2+ and Mg2+ are available. In addition, hyper-reactive cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
(C307) is involved in the binding of Mn2+ to the active site.
Plants
As discussed previously, PEPCK abundance increased when plants were watered with low-pH ammonium chloride, though high pH did not have this effect.Classification
It is classified under EC numberEC number
The Enzyme Commission number is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze....
4.1.1. There are three main types, distinguished by the source of the energy to drive the reaction:
- 4.1.1.32 - GTPGuanosine triphosphateGuanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(PCK1PCK1Phosphoenolpyruvate carboxykinase 1 , also known as PCK1, is an enzyme which in humans is encoded by the PCK1 gene.- Function:This enzyme is a main control point for the regulation of gluconeogenesis...
, PCK2) - 4.1.1.38 - diphosphate
- 4.1.1.49 - ATPAdenosine triphosphateAdenosine-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...
External links
- "mighty mice" (PEPCK-Cmus mice) http://blog.case.edu/case-news/2007/11/02/mightymouse