phosphofructokinase-2

ホスホフルクトキナーゼ2

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/04/28 16:50:28」(JST)

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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
Search PMC articles PubMed articles NCBI proteins

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
Search PMC articles PubMed articles NCBI proteins

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
SUPERFAMILY	1bif
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Phosphofructokinase 2 (PFK2) or fructose bisphosphatase 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. The 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.

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. In the liver Protein kinase A inactivates the PFK-2 domain of the bifunctional enzyme via phosphorylation, however this does not occur in skeletal muscle. The F-2,6-BPase domain is then activated 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.

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.

Regulation

The allosteric regulation of PFK2 is very similar to the regulation of PFK1. High levels of AMP or phosphate group signifies a low energy state 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 (PKA), which phosphorylates the PFK2 complex and causes its FBPase activity to be favored; via PKA and PFK2/FBP, glucagon decreases [F-2,6-BP], which inhibits glycolysis by allosteric inhibition of PFK1. Insulin activates PFK2 by activating protein phosphatase, which dephosphorylates the PFK-2 complex and causes its PFK2 activity to be favored; via Protein Phosphatase and PFK2, insulin increases [F-2,6-BP], which activates glycolysis by allosteric activation of PFK1, signalling an abundance of glucose

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:

1. Histidine acts as a nucleophile and attacks the 2-phosphate of F-2,6-BP
2. The stabilization of pentacoordinated transition state by several salt bridges and hydrogen bonding.
3. The breakdown of the transition state and the release of F6P.
4. 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 schizophrenia. Furthermore, the control of PFK2/FBPase2 activity was found to be linked to heart functioning and the control against hypoxia.

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:

• PFKFB1, PFKFB2, PFKFB3, PFKFB4

References

Further reading

• Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L (August 2004). "6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis". Biochem. J. 381 (Pt 3): 561–79. doi:10.1042/BJ20040752. PMC 1133864. PMID 15170386. 

External links

• Fructose 2,6-bisphosphatase at the US National Library of Medicine Medical Subject Headings (MeSH)
• 6-phosphofructokinase of Arabidopsis thaliana at genome.jp

UpToDate Contents

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• 1. ホスホフルクトキナーゼ欠損症（糖原病VII型、垂井病） phosphofructokinase deficiency glycogen storage disease vii tarui disease
• 2. グルコースおよびグリコーゲン代謝の遺伝性疾患の概要 overview of inherited disorders of glucose and glycogen metabolism
• 3. ホスホグリセリン酸キナーゼ欠損症およびホスホグリセリン酸ムターゼ欠損症 phosphoglycerate kinase deficiency and phosphoglycerate mutase deficiency
• 4. 代謝性ミオパチーへのアプローチ approach to the metabolic myopathies
• 5. 小児における溶血性貧血の概要 overview of hemolytic anemias in children

English Journal

• Effects of lead exposure on brain glucose metabolism and insulin signaling pathway in the hippocampus of rats.

• Yun S, Wu Y, Niu R, Feng C, Wang J.
• Toxicology letters. 2019 Aug;310()23-30.
• The aim of this study was to determine whether Pb affects glucose metabolism in the hippocampus of rats. Male Sprague-Dawley rats aged 21 days were orally administered a 0.1%, 0.2%, or 0.3% lead acetate solution in deionized water for 65 days. Then, the weight of the rats; brain Pb content; brain gl
• PMID 30980912

• Glucose and urea metabolic enzymes are differentially phosphorylated during freezing, anoxia, and dehydration exposures in a freeze tolerant frog.

• Hawkins LJ, Wang M, Zhang B, Xiao Q, Wang H, Storey KB.
• Comparative biochemistry and physiology. Part D, Genomics & proteomics. 2019 Jun;30()1-13.
• Vertebrate freeze tolerance requires multiple adaptations underpinned by specialized biochemistry. Freezing of extracellular water leads to intracellular dehydration as pure water is incorporated into growing ice crystals and also results in the cessation of blood supply to tissues, creating an anox
• PMID 30710892

• Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism.

• Vanherwegen AS, Eelen G, Ferreira GB, Ghesquière B, Cook DP, Nikolic T, Roep B, Carmeliet P, Telang S, Mathieu C, Gysemans C.
• The Journal of steroid biochemistry and molecular biology. 2019 03;187()134-145.
• Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D (1α,25-dihydroxyvitamin D; 1α,25(OH)D) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme
• PMID 30481575

Japanese Journal

• Purification and properties of phosphofructokinase 2/fructose 2,6-bisphosphatase from chicken liver and from pigeon muscle

• Eur. J. Biochem. 159, 359-365, 1986
• NAID 80003113642

Related Links

• Phosphofructokinase-2/Fructose-2,6-bisphosphatase

To understand this figure, you should know that Fructose-2,6-bisphosphate is an allosteric activator of PFK1 and, thus, controls the rate of conversion of Fructose-6-P to Fructose-1,6-biP, and, thus, the rate of glycolysis. Also ...

• Phosphofructokinase-2 | definition of Phosphofructokinase-2 ...

phosphofructokinase [fos″fo-fruk″to-ki´nās] an enzyme of the glycolytic (Embden-Meyerhof) pathway that catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. phosphofructokinase (fŏs″fō-frŭk″tō-kī′nās) A ...

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関連記事	「phosphofructokinase」

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英

phosphofructokinase-2 PFK2, phosphofructokinase 2

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6-ホスホフルクト-2-キナーゼ 6-phosphofructo-2-kinase,

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ホスホフルクトキナーゼ

「ホスホフルクトキナーゼ-2」

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英

phosphofructokinase-2

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ホスホフルクトキナーゼ2

「6-ホスホフルクト-2-キナーゼ」

　　[★] phosphofructokinase-2

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PFK2

「phosphofructokinase」

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