PFK2
Encyclopedia
Phosphofructokinase 2 (PFK2) or fructose biphosphatase 2 (FBPase2), is an enzyme
responsible for regulating the rates of glycolysis
and gluconeogenesis
in the human body
. It is a homodimer of 55 kDa subunits arranged in a head-to-head fashion, with each polypeptide chain consisting of independent kinase
and phosphatase
domain. When Ser-32 of the bifunctional protein is phosphorylated, the negative charge causes the conformation change of the enzyme to favor the FBPase2 activity; otherwise, PFK2 activity is favored. PFK2 domain is closely related to the superfamily of mononucleotide binding proteins including adenylate cyclase
, whereas that of FBPase2 is related to a family of proteins that include phosphoglycerate mutase
s.
On the other hand, the phosphatase domain is located on the C-terminal. It resembles the family of proteins that include phosphoglycerate mutases (PGMs) and acid phosphatases. The domain has a mixed α/ β structure, with a six-stranded central β sheet, plus an additional α-helical subdomain that covers the presumed active site of the molecule. Finally, N-terminal region modulates PFK2 and FBPase2 activities, and stabilizes the dimer form of the enzyme.
(F-2,6-BP) levels. Because F-2,6-BP normally stimulates phosphofructokinase-1(PFK1), the decrease in its concentration leads to the inhibition of glycolysis and the stimulation of gluconeogenesis.
On the other hand, when the glucose level increases, the level of fructose 6-phosphate
(F6P) subsequently rises and the molecule stimulates phosphoprotein phosphatase-1
, which removes phosphoryl group from the bifunctional protein. So PFK2 domain is activated and the kinase catalyzes the formation of F-2,6-BP. Thus, glycolysis is stimulated and gluconeogenesis is inhibited.
or phosphate group signifies low levels of glucose and thus stimulates PFK2. On the other hand, a high concentration of phosphoenolpyruvate
(PEP) and citrate
signifies that there is a high level of biosynthetic precursor and hence inhibits PFK2. However, unlike PFK1, PFK2 is not affected by the ATP concentration.
Glucagon inhibits PFK2 by activating Protein Kinase A, causing the FBPase activity to be favored, decreasing [F-2,6-BP], and thereby inhibiting glycolysis through the inhibition of PFK1.
The hydrolysis of fructose 2,6-biphosphate is likely to follow the below steps:
. Furthermore, the control of PFK2/FBPase2 activity was found to be linked to heart functioning and the control against hypoxia
.
Humans genes encoding proteins possessing phosphofructokinase 2 activity include:
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...
responsible for regulating the rates of glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
and 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....
in the human body
Human body
The human body is the entire structure of a human organism, and consists of a head, neck, torso, two arms and two legs.By the time the human reaches adulthood, the body consists of close to 100 trillion cells, the basic unit of life...
. It is a homodimer of 55 kDa subunits arranged in a head-to-head fashion, with each polypeptide chain consisting of independent kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
and phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
domain. When Ser-32 of the bifunctional protein is phosphorylated, the negative charge causes the conformation change of the enzyme to favor the FBPase2 activity; otherwise, PFK2 activity is favored. PFK2 domain is closely related to the superfamily of mononucleotide binding proteins including adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
, whereas that of FBPase2 is related to a family of proteins that include phosphoglycerate mutase
Phosphoglycerate mutase
-Overview:Phosphoglycerate mutase is an enzyme that catalyzes step 8 of glycolysis. It catalyzes the internal transfer of a phosphate group from C-3 to C-2 which results in the conversion of 3-phosphoglycerate to 2-phosphoglycerate through a 2,3-bisphosphoglycerate intermediate.This enzyme is...
s.
Structure
The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N-terminal. It consists of a central six-stranded β sheet, with five parallel strands and an antiparallel edge strand, surrounded by seven α helices. The domain contains nucleotide-binding fold (nbf) at the C-terminal end of the first β-strand, and thus resembles the structure of adenylate kinase.On the other hand, the phosphatase domain is located on the C-terminal. It resembles the family of proteins that include phosphoglycerate mutases (PGMs) and acid phosphatases. The domain has a mixed α/ β structure, with a six-stranded central β sheet, plus an additional α-helical subdomain that covers the presumed active site of the molecule. Finally, N-terminal region modulates PFK2 and FBPase2 activities, and stabilizes the dimer form of the enzyme.
Function
When glucose level is low, glucagon is released into the bloodstream, triggering a cAMP signal cascade. Protein kinase A thus activated phosphorylates the bifunctional enzyme, activating FBPase2 which lowers fructose 2,6-bisphosphateFructose 2,6-bisphosphate
Fructose 2,6-bisphosphate abbreviated Fru-2,6-P2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 and fructose 1,6-bisphosphatase to regulate glycolysis and gluconeogenesis...
(F-2,6-BP) levels. Because F-2,6-BP normally stimulates phosphofructokinase-1(PFK1), the decrease in its concentration leads to the inhibition of glycolysis and the stimulation of gluconeogenesis.
On the other hand, when the glucose level increases, the level of fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
(F6P) subsequently rises and the molecule stimulates phosphoprotein phosphatase-1
PPP1R1B
Protein phosphatase 1 regulatory subunit 1B , also known as dopamine- and cAMP-regulated neuronal phosphoprotein , is a protein that in humans is encoded by the PPP1R1B gene.- Function :...
, which removes phosphoryl group from the bifunctional protein. So PFK2 domain is activated and the kinase catalyzes the formation of F-2,6-BP. Thus, glycolysis is stimulated and gluconeogenesis is inhibited.
Regulation
The allosteric regulation of PFK2 is very similar to the regulation of PFK1. High levels of AMPAdenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
or phosphate group signifies low levels of glucose and thus stimulates PFK2. On the other hand, a high concentration of 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 citrate
Citrate
A 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:...
signifies that there is a high level of biosynthetic precursor and hence inhibits PFK2. However, unlike PFK1, PFK2 is not affected by the ATP concentration.
Glucagon inhibits PFK2 by activating Protein Kinase A, causing the FBPase activity to be favored, decreasing [F-2,6-BP], and thereby inhibiting glycolysis through the inhibition of PFK1.
Reaction mechanism
PFK2 is likely to catalyze the "simple" transfer of γ-phosphoryl group of ATP onto the hydroxyl present on C-2 of fructose-6-phosphate. Yet, the formation of fructose 2,6-bisphosphate could theoretically occur by a variety of mechanisms, including the intermediary formation of Fructose-6-phosphate 2-pyrophosphate.The hydrolysis of fructose 2,6-biphosphate is likely to follow the below steps:
- Histidine acts as a nucleophile and attacks the 2-phosphate of F-2,6-BP
- The stabilization of pentacoordinated transition state by several salt bridges and hydrogen bonding.
- The breakdown of the transition state and the release of F6P.
- Histidine increases the nucleophilicity of water, which attacks phosphohistidine, generating phosphate and newly protonated histidine.
Clinical significance
The Pfkfb2 gene encoding PFK2/FBPase2 protein is linked to the predisposition to schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. Furthermore, the control of PFK2/FBPase2 activity was found to be linked to heart functioning and the control against hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
.
Isozymes
Five mammalian isozymes of the protein have been reported to date, difference rising by either the transcription of different enzymes or alternative splicing.The isozymes differ radically in their regulation and the discussions above are based on liver isozyme.Humans genes encoding proteins possessing phosphofructokinase 2 activity include:
- PFKFB1PFKFB16-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 is an enzyme that in humans is encoded by the PFKFB1 gene.-Further reading:...
, PFKFB2PFKFB26-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 is an enzyme that in humans is encoded by the PFKFB2 gene.-Further reading:...
, PFKFB3PFKFB36-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 is an enzyme that in humans is encoded by the PFKFB3 gene.-Further reading:...
, PFKFB4PFKFB46-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 also known as PFKFB4 is a enzyme which in humans is encoded by the PFKFB4 gene.- Function :...