| 6-phosphofructo-2-kinase | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| EC number | 2.7.1.105 | ||||||
| CAS number | 78689-77-7 | ||||||
| Databases | |||||||
| IntEnz | IntEnz view | ||||||
| BRENDA | BRENDA entry | ||||||
| ExPASy | NiceZyme view | ||||||
| KEGG | KEGG entry | ||||||
| MetaCyc | metabolic pathway | ||||||
| PRIAM | profile | ||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||
| Gene Ontology | AmiGO / EGO | ||||||
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| fructose-2,6-bisphosphate 2-phosphatase | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| EC number | 3.1.3.46 | ||||||
| CAS number | 81611-75-8 | ||||||
| Databases | |||||||
| IntEnz | IntEnz view | ||||||
| BRENDA | BRENDA entry | ||||||
| ExPASy | NiceZyme view | ||||||
| KEGG | KEGG entry | ||||||
| MetaCyc | metabolic pathway | ||||||
| PRIAM | profile | ||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||
| Gene Ontology | AmiGO / EGO | ||||||
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| 6-phosphofructo-2-kinase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Structure of PFK2. Shown: kinase domain (cyan) and the phosphatase domain (green). | |||||||||
| Identifiers | |||||||||
| Symbol | 6PF2K | ||||||||
| Pfam | PF01591 | ||||||||
| InterPro | IPR013079 | ||||||||
| PROSITE | PDOC00158 | ||||||||
| SCOP | 1bif | ||||||||
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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.[1] 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 mutases.
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The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N-terminal.[2] It consists of a central six-stranded β sheet, with five parallel strands and an antiparallel edge strand, surrounded by seven α helices.[3] The domain contains nucleotide-binding fold (nbf) at the C-terminal end of the first β-strand,[4] and thus resembles the structure of adenylate kinase.
On the other hand, the phosphatase domain is located on the C-terminal.[5] It resembles the family of proteins that include phosphoglycerate mutases (PGMs) and acid phosphatases.[6] 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.[3] Finally, N-terminal region modulates PFK2 and FBPase2 activities, and stabilizes the dimer form of the enzyme.[6][7]
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-bisphosphate (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.[8]
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.
The allosteric regulation of PFK2 is very similar to the regulation of PFK1.[9] High levels of AMP 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.
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.[9]
The hydrolysis of fructose 2,6-biphosphate is likely to follow the below steps:[10]
The Pfkfb2 gene encoding PFK2/FBPase2 protein is linked to the predisposition to schizophrenia.[11] Furthermore, the control of PFK2/FBPase2 activity was found to be linked to heart functioning and the control against hypoxia.[12]
Five mammalian isozymes of the protein have been reported to date, difference rising by either the transcription of different enzymes or alternative splicing.[13][14][15]The isozymes differ radically in their regulation and the discussions above are based on liver isozyme.[3]
Humans genes encoding proteins possessing phosphofructokinase 2 activity include:
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