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27  structures 1024  species 3  interactions 3821  sequences 66  architectures

Family: 6PF2K (PF01591)

Summary: 6-phosphofructo-2-kinase

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This is the Wikipedia entry entitled "6-phosphofructo-2-kinase". More...

6-phosphofructo-2-kinase Edit Wikipedia article

6-phosphofructo-2-kinase
5htk.jpg
6-phosphofructo-2-kinase dimer, Human heart
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 / QuickGO
6PF2K
PDB 1k6m EBI.jpg
crystal structure of human liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
Identifiers
Symbol 6PF2K
Pfam PF01591
Pfam clan CL0023
InterPro IPR013079
PROSITE PDOC00158
SCOP 1bif
SUPERFAMILY 1bif


Thus, the two substrates of this enzyme are ATP and beta-D-fructose 6-phosphate, whereas its two products are ADP and beta-D-fructose 2,6-bisphosphate.

The systematic name of this enzyme class is ATP:beta-D-fructose-6-phosphate 2-phosphotransferase. Other names in common use include phosphofructokinase 2, 6-phosphofructose 2-kinase, 6-phosphofructo-2-kinase (phosphorylating), fructose 6-phosphate 2-kinase, and ATP:D-fructose-6-phosphate 2-phosphotransferase. This enzyme participates in fructose and mannose metabolism. The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity.[1] The family described here bears a resemblance to the ATP-driven phospho-fructokinases, however, they share little sequence similarity, although a few residues seem key to their interaction with fructose 6-phosphate.[2]


References

  1. ^ Heine-Suñer D, Díaz-Guillén MA, Lange AJ, Rodríguez de Córdoba S (May 1998). "Sequence and structure of the human 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase heart isoform gene (PFKFB2)". Eur. J. Biochem. 254 (1): 103–10. doi:10.1046/j.1432-1327.1998.2540103.x. PMID 9652401. 
  2. ^ Wang X, Deng Z, Kemp RG (September 1998). "An essential methionine residue involved in substrate binding by phosphofructokinases". Biochem. Biophys. Res. Commun. 250 (2): 466–8. doi:10.1006/bbrc.1998.9311. PMID 9753654. 
  • Van Schaftingen E, Hers HG (1981). "Phosphofructokinase 2: the enzyme that forms fructose 2,6-bisphosphate from fructose 6-phosphate and ATP". Biochem. Biophys. Res. Commun. 101 (3): 1078–84. doi:10.1016/0006-291X(81)91859-3. PMID 6458291. 

This article incorporates text from the public domain Pfam and InterPro IPR013079


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This is the Wikipedia entry entitled "Phosphofructokinase 2". More...

Phosphofructokinase 2 Edit Wikipedia article

6-phosphofructo-2-kinase/fructose-bisphosphatase-2
Phosphofructokinase 2.jpg
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
fructose-bisphosphatase-2
Identifiers
Symbol FBPase-2
Pfam PF00316
InterPro IPR028343
PROSITE PDOC00114

Phosphofructokinase-2 (6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation of a significant allosteric regulator, fructose-2,6-bisphosphate (Fru-2,6-P2) from substrate fructose-6-phosphate. Fru-2,6-P2 contributes to the rate-determining step of glycolysis as it activates enzyme Phosphofructokinase 1 in the glycolysis pathway, and inhibits fructose-1,6-bisphosphatase 1 in gluconeogenesis.[1] Since Fru-2,6-P2 differentially regulates glycolysis and gluconeogenesis, it can act as a key signal to switch between the opposing pathways.[1] Because PFK-2 produces Fru-2,6-P2 in response to hormonal signaling, metabolism can be more sensitively and efficiently controlled to align with the organism's glycolytic needs.[2]

PFK-2 is known as the "bifunctional enzyme" because of its notable structure: though both are located on one protein homodimer, its two domains act as independently functioning enzymes.[3] One terminus serves as a kinase domain (for PFK-2) while the other terminus acts as a phosphatase domain (FBPase-2).[4]

In mammals, genetic mechanisms encode different PFK-2 isoforms to accommodate tissue specific needs. While general function remains the same, isoforms feature slight differences in enzymatic properties and are controlled by different methods of regulation; these differences are discussed below.[5]

Structure

The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N-terminal.[6] It consists of a central six-stranded β sheet, with five parallel strands and an antiparallel edge strand, surrounded by seven α helices.[4] The domain contains nucleotide-binding fold (nbf) at the C-terminal end of the first β-strand.[7] The PFK-2 domain appears to be closely related to the superfamily of mononucleotide binding proteins including adenylate cyclase.[8]

On the other hand, the phosphatase domain is located on the C-terminal.[9] It resembles the family of proteins that include phosphoglycerate mutases and acid phosphatases.[8][10] 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.[4] Finally, the N-terminal region modulates PFK-2 and FBPase2 activities, and stabilizes the dimer form of the enzyme.[10][11]

While this central catalytic core remains conserved in all forms of PFK-2, slight structural variations exist in isoforms as a result of different amino acid sequences or alternative splicing.[12] With some minor exceptions, the size of PFK-2 enzymes is typically around 55 kDa.[1]

Researchers hypothesize that the unique bifunctional structure of this enzyme arose from a gene fusion event between a primordial bacterial PFK-1 and a primordial mutase/phosphatase.[13]

Function

This enzyme's main function is to synthesize or degrade allosteric regulator Fru-2,6-P2 in response to glycolytic needs of the cell or organism, as depicted in the accompanying diagram.

PFK-2 and FBPase-2 Reaction

In enzymology, a 6-phosphofructo-2-kinase (EC 2.7.1.105) is an enzyme that catalyzes the chemical reaction:

ATP + beta-D-fructose 6-phosphate ADP + beta-D-fructose 2,6-bisphosphate[14]

Thus, the kinase domain hydrolyzes ATP to phosphorylate the carbon-2 of fructose-6-phosphate, producing Fru-2,6-P2 and ADP. A phosphohistidine intermediate is formed within the reaction.[15]

At the other terminal, the fructose-2,6-bisphosphate 2-phosphatase (EC 3.1.3.46) domain dephosphorylates Fru-2,6-P2 with the addition of water. This opposing chemical reaction is:
beta-D-fructose 2,6-bisphosphate + H2O D-fructose 6-phosphate + phosphate[16]

Because of the enzyme's dual functions, it can be categorized into multiple families. Through categorization by the kinase reaction, this enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing groups (phosphotransferases) with an alcohol group as acceptor.[14] On the other hand, the phosphatase reaction is characteristic of the family of hydrolases, specifically those acting on phosphoric monoester bonds.[16]

Regulation

In almost all isoforms, PFK-2 undergoes covalent modification through phosphorylation/dephosphorylation based on the cell's hormonal signaling. Phosphorylation of a specific residue may prompt a shift that stabilizes either kinase or phosphatase domain function. This regulation signal thus controls whether F-2,6-P2 will be synthesized or degraded.[17]

Furthermore, the allosteric regulation of PFK2 is very similar to the regulation of PFK1.[18] High levels of AMP or phosphate group signifies a low energy charge 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. Unlike PFK1, PFK2 is not affected by ATP concentration.[19]

Isozymes

Protein isozymes are enzymes that catalyze the same reaction but are encoded with different amino acid sequences and as such, display slight differences in protein characteristics. In humans, the four genes that encode phosphofructokinase 2 proteins include PFKFB-1, PFKFB2, PFKFB3 and PFKFB4.[3]

Multiple mammalian isoforms of the protein have been reported to date, difference rising by either the transcription of different enzymes or alternative splicing.[20][21][22] While the structural core that catalyzes the PFK-2/FBPase-2 reaction is highly conserved across isoforms, the major differences arise from highly variable flanking sequences in the isoform amino and carboxyl terminals.[12] Because these areas often contain phosphorylation sites, changes in amino acid composition or terminal length may result in vastly different enzyme kinetics and characteristics.[1][12] Each variant differs in their primary tissue of expression, response to protein kinase regulation, and ratio of kinase/phosphatase domain activity.[23] While multiple types of isozymes may consist in a tissue, isozymes are identified by their primary tissue expression and tissue of discovery below.[24]

PFKB1: Liver, muscle, and fetal

6-phosophofructo-2-kinase: PFKB1
PDB 1k6m EBI.jpg
Crystal structure of human liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
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 / QuickGO

Located on the X chromosome, this gene is the most well-known of the four genes particularly because it encodes the highly researched liver enzyme.[20] Variable mRNA splicing of PFKB1 yields three different promoters (L, M and F) and therefore, three tissue-specific variants that differ in regulation:[25]

  • L-Type: liver tissue
    • Insulin activates liver PFK-2 function to indicate a high abundance of blood glucose is available for glycolysis. Insulin activates a protein phosphatase which dephosphorylates the PFK-2 complex and causes favored PFK-2 activity. PFK-2 then increases production of F-2,6-P2. As this product allosterically activates PFK-1, it activates glycolysis and inhibits gluconeogenesis.[26]
    • In contrast, glucagon increases FBPase-2 activity. At low blood glucose concentrations, glucagon triggers a cAMP signal cascade and in turn, Protein Kinase A (PKA) phosphorylates Serine 32 near the N-terminus. This inactivates the bifunctional enzyme's ability to act as a kinase and stabilizes the phosphatase activity. Therefore, glucagon decreases concentrations of F-2,6-P2, slows rates of glycolysis, and stimulates the gluconeogenesis pathway.[27][28]
Liver-Tissue PFK-2 Regulation: Concentrations of hormones glucagon and insulin activate proteins which change phosphorylation state of PFK-2. Depending on which domain is stabilized, PFK-2 will synthesize or degrade fructose-2,6-bisphosphate, which impacts rates of glycolysis.
  • M-Type: skeletal muscle tissue; F-Type: fibroblast and fetal tissue[29]
    • In contrast to most other PFK-2 tissues, PFK-2 in both skeletal muscle and fetal tissue is solely regulated by concentrations of Fructose-6-phosphate. Within their first exon, there are no regulatory sites that require phosphorylation/dephosphorylation to provoke a change in function. High concentrations of F-6-P will activate kinase function and increase rates of glycolysis, whereas low concentrations of F-6-P will stabilize phosphatase action.[25]
6-phosophofructo-2-kinase: PFKB2
5htk.jpg
6-phosphofructo-2-kinase dimer, Human heart tissue
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 / QuickGO

PFKB2: Cardiac (H-Type)

The PFKB2 gene is located on chromosome 1.[30] When greater concentrations of adrenaline and/or insulin hormone are circulated, a Protein Kinase A pathway is activated which phosphorylates either Serine 466 or Serine 483 in the C-terminus.[31] Alternatively, Protein Kinase B may also phosphorylate these regulatory sites, which are part of the FBPase-2 domain.[32] When this serine residue is phosphorylated, FBPase-2 function is inactivated and greater PFK-2 activity is stabilized.[25]

PFKB3: Brain, placental, and inducible

PFKB3 is located on chromosome 10 and transcribes two major isoforms, inducible type and ubiquitous type.[33] These forms differ in alternative splicing of Exon 15 in their C-terminus.[34] However, they are similar in that for both, insulin activates a cyclic AMP pathway; this results in Protein Kinase A, Protein Kinase C, or AMP-activated Protein Kinase phosphorylating a regulatory residue on Serine 461 in the C-terminus to stabilize PFK-2 kinase function.[35] Furthermore, both isoforms transcribed from this gene are noted for having a particularly high, dominant rate of kinase activity as indicated by a kinase/phosphatase activity ratio of 700 (whereas the liver, heart, and testis isozymes respectively have PFK-2/FBPase-2 ratios of 1.5, 80, and 4).[36] Therefore, PFKB3 in particular consistently produces large amounts of F-2,6-P2 and sustains high rates of glycolysis.[36][37]

  • I-Type: Inducible
    • This isoform's name is a result of its increased expression in response to hypoxic stress; its formation is induced by lack of oxygen. This type is highly expressed in rapidly proliferating cells, especially tumor cells.[38]
  • U-Type: Ubiquitous;[39] also known as placental[40] or brain[41][42]
    • Though discovered separately in the placental, pancreatic-β-islet, or brain tissues, the various isoforms appear identical.[19] The tissues it was discovered in all require great energy to function, which may explain PFKB3's advantage of such high kinase-phosphatase activity ratio.[36][43]
    • The brain isoform in particular has lengthy N- and C-terminus regions such that this type is almost twice as large as the typical PFK-2, at around 110 kDa.[44]
i-PFKB3, Human inducible form

PFKB4: Testis (T-Type)

Gene PFKB4, located on chromosome 3, expresses PFK-2 in human testis tissue.[45] PFK-2 enzymes encoded by PFK-4 are comparable to the liver enzyme in size at around 54kDa, and like the muscle tissue, do not contain a protein kinase phosphorylation site.[39] While less research has clarified regulation mechanisms for this isoform, studies have confirmed that modification from multiple transcription factors in the 5' flanking region regulates the amount of PFK-2 expression in developing testis tissue.[24] This isoform has been particularly implicated as being modified and hyper-expressed for prostate cancer cell survival.[46]

6-phosphofructo-2-kinase structure, testis tissue

Clinical significance

Because this enzyme family maintains rates of glycolysis and gluconeogenesis, it presents great potential for therapeutic action for control of metabolism particularly in diabetes and cancer cells.[4][23] Data also demonstrates that all of the PFK-2 genes (although the PFKB3 gene response remains the most drastic) were activated by limitations in oxygen.[47] The control of PFK-2/FBP-ase2 activity was found to be linked to heart functioning, particularly for ischemia, and the control against hypoxia.[48] Researchers hypothesize that this responsive characteristic of the PFK-2 genes may be a strong, evolutionary physiological adaptation.[47] However, many human cancer cell types (including leukemia, lung, breast, colon, pancreatic, and ovarian cancers) demonstrate over-expression of PFK3 and/or PFK4; this change in metabolism likely plays a role in the Warburg effect.[23][49]

Lastly, the Pfkfb2 gene encoding PFK2/FBPase2 protein is linked to the predisposition to schizophrenia.[50]

References

  1. ^ a b c d Kurland IJ, Pilkis SJ (June 1995). "Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme". Protein Science. 4 (6): 1023–37. doi:10.1002/pro.5560040601. PMC 2143155Freely accessible. PMID 7549867. 
  2. ^ Lenzen S (May 2014). "A fresh view of glycolysis and glucokinase regulation: history and current status". The Journal of Biological Chemistry. 289 (18): 12189–94. doi:10.1074/jbc.R114.557314. PMC 4007419Freely accessible. PMID 24637025. 
  3. ^ a b 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". The Biochemical Journal. 381 (Pt 3): 561–79. doi:10.1042/BJ20040752. PMC 1133864Freely accessible. PMID 15170386. 
  4. ^ a b c d Hasemann CA, Istvan ES, Uyeda K, Deisenhofer J (September 1996). "The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies". Structure. 4 (9): 1017–29. doi:10.1016/S0969-2126(96)00109-8. PMID 8805587. 
  5. ^ Atsumi T, Nishio T, Niwa H, Takeuchi J, Bando H, Shimizu C, Yoshioka N, Bucala R, Koike T (December 2005). "Expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase/PFKFB3 isoforms in adipocytes and their potential role in glycolytic regulation". Diabetes. 54 (12): 3349–57. doi:10.2337/diabetes.54.12.3349. PMID 16306349. 
  6. ^ Kurland I, Chapman B, Lee YH, Pilkis S (August 1995). "Evolutionary reengineering of the phosphofructokinase active site: ARG-104 does not stabilize the transition state in 6-phosphofructo-2-kinase". Biochemical and Biophysical Research Communications. 213 (2): 663–72. doi:10.1006/bbrc.1995.2183. PMID 7646523. 
  7. ^ Walker JE, Saraste M, Runswick MJ, Gay NJ (1982). "Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold". The EMBO Journal. 1 (8): 945–51. PMC 553140Freely accessible. PMID 6329717. 
  8. ^ a b Jedrzejas MJ (2000). "Structure, function, and evolution of phosphoglycerate mutases: comparison with fructose-2,6-bisphosphatase, acid phosphatase, and alkaline phosphatase". Progress in Biophysics and Molecular Biology. 73 (2-4): 263–87. doi:10.1016/S0079-6107(00)00007-9. PMID 10958932. 
  9. ^ Li L, Lin K, Pilkis J, Correia JJ, Pilkis SJ (October 1992). "Hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. The role of surface loop basic residues in substrate binding to the fructose-2,6-bisphosphatase domain". The Journal of Biological Chemistry. 267 (30): 21588–94. PMID 1328239. 
  10. ^ a b Stryer L, Berg JM, Tymoczko JL (2008). "The Balance Between Glycolysis and Gluconeogenesis in the Liver Is Sensitive to Blood-Glucose Concentration". Biochemistry (Looseleaf). San Francisco: W. H. Freeman. pp. 466–467. ISBN 978-1-4292-3502-0. 
  11. ^ Tominaga N, Minami Y, Sakakibara R, Uyeda K (July 1993). "Significance of the amino terminus of rat testis fructose-6-phosphate, 2-kinase:fructose-2,6-bisphosphatase". The Journal of Biological Chemistry. 268 (21): 15951–7. PMID 8393455. 
  12. ^ a b c El-Maghrabi MR, Noto F, Wu N, Manes N (September 2001). "6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: suiting structure to need, in a family of tissue-specific enzymes". Current Opinion in Clinical Nutrition and Metabolic Care. 4 (5): 411–8. PMID 11568503. 
  13. ^ Bazan JF, Fletterick RJ, Pilkis SJ (December 1989). "Evolution of a bifunctional enzyme: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase". Proceedings of the National Academy of Sciences of the United States of America. 86 (24): 9642–6. PMC 298557Freely accessible. PMID 2557623. 
  14. ^ a b "ENZYME entry 2.7.1.105". enzyme.expasy.org. Retrieved 2018-03-24. 
  15. ^ "6-phosphofructo-2-kinase (IPR013079)". InterPro. EMBL-EBI. Retrieved 2018-03-25. 
  16. ^ a b "ENZYME entry 3.1.3.46". enzyme.expasy.org. Retrieved 2018-03-25. 
  17. ^ Okar DA, Manzano A, Navarro-Sabatè A, Riera L, Bartrons R, Lange AJ (January 2001). "PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate". Trends in Biochemical Sciences. 26 (1): 30–5. PMID 11165514. 
  18. ^ Van Schaftingen E, Hers HG (August 1981). "Phosphofructokinase 2: the enzyme that forms fructose 2,6-bisphosphate from fructose 6-phosphate and ATP". Biochemical and Biophysical Research Communications. 101 (3): 1078–84. doi:10.1016/0006-291X(81)91859-3. PMID 6458291. 
  19. ^ a b Ros S, Schulze A (February 2013). "Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism". Cancer & Metabolism. 1 (1): 8. doi:10.1186/2049-3002-1-8. PMC 4178209Freely accessible. PMID 24280138. 
  20. ^ a b Darville MI, Crepin KM, Hue L, Rousseau GG (September 1989). "5' flanking sequence and structure of a gene encoding rat 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase". Proceedings of the National Academy of Sciences of the United States of America. 86 (17): 6543–7. doi:10.1073/pnas.86.17.6543. PMC 297880Freely accessible. PMID 2549541. 
  21. ^ Tsuchiya Y, Uyeda K (May 1994). "Bovine heart fructose 6-P,2-kinase:fructose 2,6-bisphosphatase mRNA and gene structure". Archives of Biochemistry and Biophysics. 310 (2): 467–74. doi:10.1006/abbi.1994.1194. PMID 8179334. 
  22. ^ Sakata J, Abe Y, Uyeda K (August 1991). "Molecular cloning of the DNA and expression and characterization of rat testes fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase". The Journal of Biological Chemistry. 266 (24): 15764–70. PMID 1651918. 
  23. ^ a b c Novellasdemunt L, Tato I, Navarro-Sabate A, Ruiz-Meana M, Méndez-Lucas A, Perales JC, Garcia-Dorado D, Ventura F, Bartrons R, Rosa JL (April 2013). "Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids". The Journal of Biological Chemistry. 288 (15): 10640–51. doi:10.1074/jbc.M113.455998. PMC 3624444Freely accessible. PMID 23457334. 
  24. ^ a b Gómez M, Manzano A, Navarro-Sabaté A, Duran J, Obach M, Perales JC, Bartrons R (January 2005). "Specific expression of pfkfb4 gene in spermatogonia germ cells and analysis of its 5'-flanking region". FEBS Letters. 579 (2): 357–62. doi:10.1016/j.febslet.2004.11.096. PMID 15642344. 
  25. ^ a b c Salway JG (2017). Metabolism at a Glance. Wiley-Blackwell. ISBN 978-0-470-67471-0. 
  26. ^ Hue L, Rider MH, Rousseau GG (1990). "Fructose-2,6-bisphosphate in extra hepatic tissues". In Pilkis SJ. Fructose-2,6-bisphosphate. Boca Raton, Fla.: CRC Press. pp. 173–193. ISBN 978-0-8493-4795-5. 
  27. ^ Pilkis SJ, el-Maghrabi MR, Claus TH (1988). "Hormonal regulation of hepatic gluconeogenesis and glycolysis". Annual Review of Biochemistry. 57: 755–83. doi:10.1146/annurev.bi.57.070188.003543. PMID 3052289. 
  28. ^ Marker AJ, Colosia AD, Tauler A, Solomon DH, Cayre Y, Lange AJ, el-Maghrabi MR, Pilkis SJ (April 1989). "Glucocorticoid regulation of hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression". The Journal of Biological Chemistry. 264 (12): 7000–4. PMID 2540168. 
  29. ^ Cosin-Roger J, Vernia S, Alvarez MS, Cucarella C, Boscá L, Martin-Sanz P, Fernández-Alvarez AJ, Casado M (February 2013). "Identification of a novel Pfkfb1 mRNA variant in rat fetal liver". Biochemical and Biophysical Research Communications. 431 (1): 36–40. doi:10.1016/j.bbrc.2012.12.109. PMID 23291237. 
  30. ^ Darville MI, Chikri M, Lebeau E, Hue L, Rousseau GG (August 1991). "A rat gene encoding heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase". FEBS Letters. 288 (1-2): 91–4. PMID 1652483. 
  31. ^ Heine-Suñer D, Díaz-Guillén MA, Lange AJ, Rodríguez de Córdoba S (May 1998). "Sequence and structure of the human 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase heart isoform gene (PFKFB2)". European Journal of Biochemistry. 254 (1): 103–10. PMID 9652401. 
  32. ^ Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L (October 2000). "Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia". Current Biology. 10 (20): 1247–55. PMID 11069105. 
  33. ^ Navarro-Sabaté A, Manzano A, Riera L, Rosa JL, Ventura F, Bartrons R (February 2001). "The human ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene (PFKFB3): promoter characterization and genomic structure". Gene. 264 (1): 131–8. doi:10.1016/S0378-1119(00)00591-6. PMID 11245987. 
  34. ^ Riera L, Manzano A, Navarro-Sabaté A, Perales JC, Bartrons R (April 2002). "Insulin induces PFKFB3 gene expression in HT29 human colon adenocarcinoma cells". Biochimica et Biophysica Acta. 1589 (2): 89–92. doi:10.1016/S0167-4889(02)00169-6. PMID 12007784. 
  35. ^ Marsin AS, Bouzin C, Bertrand L, Hue L (August 2002). "The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase". The Journal of Biological Chemistry. 277 (34): 30778–83. doi:10.1074/jbc.M205213200. PMID 12065600. 
  36. ^ a b c Sakakibara R, Kato M, Okamura N, Nakagawa T, Komada Y, Tominaga N, Shimojo M, Fukasawa M (July 1997). "Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase". Journal of Biochemistry. 122 (1): 122–8. PMID 9276680. 
  37. ^ Manes NP, El-Maghrabi MR (June 2005). "The kinase activity of human brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is regulated via inhibition by phosphoenolpyruvate". Archives of Biochemistry and Biophysics. 438 (2): 125–36. doi:10.1016/j.abb.2005.04.011. PMID 15896703. 
  38. ^ Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y, Han JH, Metz C, Bucala R (March 1999). "An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect". Proceedings of the National Academy of Sciences of the United States of America. 96 (6): 3047–52. PMC 15892Freely accessible. PMID 10077634. 
  39. ^ a b Manzano A, Rosa JL, Ventura F, Pérez JX, Nadal M, Estivill X, Ambrosio S, Gil J, Bartrons R (1998). "Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase gene (PFKFB3)". Cytogenetics and Cell Genetics. 83 (3-4): 214–7. doi:10.1159/000015181. PMID 10072580. 
  40. ^ Sakai A, Kato M, Fukasawa M, Ishiguro M, Furuya E, Sakakibara R (March 1996). "Cloning of cDNA encoding for a novel isozyme of fructose 6-phosphate, 2-kinase/fructose 2,6-bisphosphatase from human placenta". Journal of Biochemistry. 119 (3): 506–11. PMID 8830046. 
  41. ^ Ventura F, Ambrosio S, Bartrons R, el-Maghrabi MR, Lange AJ, Pilkis SJ (April 1995). "Cloning and expression of a catalytic core bovine brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase". Biochemical and Biophysical Research Communications. 209 (3): 1140–8. PMID 7733968. 
  42. ^ Bando H, Atsumi T, Nishio T, Niwa H, Mishima S, Shimizu C, Yoshioka N, Bucala R, Koike T (August 2005). "Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer". Clinical Cancer Research. 11 (16): 5784–92. doi:10.1158/1078-0432.CCR-05-0149. PMID 16115917. 
  43. ^ Riera L, Obach M, Navarro-Sabaté A, Duran J, Perales JC, Viñals F, Rosa JL, Ventura F, Bartrons R (August 2003). "Regulation of ubiquitous 6-phosphofructo-2-kinase by the ubiquitin-proteasome proteolytic pathway during myogenic C2C12 cell differentiation". FEBS Letters. 550 (1-3): 23–9. PMID 12935880. 
  44. ^ Ventura F, Rosa JL, Ambrosio S, Pilkis SJ, Bartrons R (September 1992). "Bovine brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Evidence for a neural-specific isozyme". The Journal of Biological Chemistry. 267 (25): 17939–43. PMID 1325453. 
  45. ^ Manzano A, Pérez JX, Nadal M, Estivill X, Lange A, Bartrons R (March 1999). "Cloning, expression and chromosomal localization of a human testis 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene". Gene. 229 (1-2): 83–9. PMID 10095107. 
  46. ^ Ros S, Santos CR, Moco S, Baenke F, Kelly G, Howell M, Zamboni N, Schulze A (April 2012). "Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival". Cancer Discovery. 2 (4): 328–43. doi:10.1158/2159-8290.CD-11-0234. PMID 22576210. 
  47. ^ a b Minchenko, O., Opentanova, I., & Caro, J. (2003). Hypoxic regulation of the 6‐phosphofructo‐2‐kinase/fructose‐2, 6‐bisphosphatase gene family (PFKFB‐1–4) expression in vivo. FEBS Letters, 554(3), 264-270.
  48. ^ Wang Q, Donthi RV, Wang J, Lange AJ, Watson LJ, Jones SP, Epstein PN (June 2008). "Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia". American Journal of Physiology. Heart and Circulatory Physiology. 294 (6): H2889–97. doi:10.1152/ajpheart.91501.2007. PMC 4239994Freely accessible. PMID 18456722. 
  49. ^ Minchenko OH, Opentanova IL, Ogura T, Minchenko DO, Komisarenko SV, Caro J, Esumi H (2005). "Expression and hypoxia-responsiveness of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 in mammary gland malignant cell lines". Acta Biochimica Polonica. 52 (4): 881–8. PMID 16025159. 
  50. ^ Stone WS, Faraone SV, Su J, Tarbox SI, Van Eerdewegh P, Tsuang MT (May 2004). "Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 127B (1): 5–10. doi:10.1002/ajmg.b.20132. PMID 15108172. 

External links

This article incorporates text from the public domain Pfam and InterPro IPR013079

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

6-phosphofructo-2-kinase Provide feedback

This enzyme occurs as a bifunctional enzyme with fructose-2,6-bisphosphatase. The bifunctional enzyme catalyses both the synthesis and degradation of fructose-2,6-bisphosphate, a potent regulator of glycolysis [1]. This enzyme contains a P-loop motif.

Literature references

  1. Hasemann CA, Istvan ES, Uyeda K, Deisenhofer J; , Structure 1996;4:1017-1029.: The crystal structure of the bifunctional enzyme 6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies. PUBMED:8805587 EPMC:8805587


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR013079

6-Phosphofructo-2-kinase (EC, EC) is a bifunctional enzyme that catalyses both the synthesis and the degradation of fructose-2, 6-bisphosphate. The fructose-2,6-bisphosphatase reaction involves a phosphohistidine intermediate. The catalytic pathway is: ATP + D-fructose 6-phosphate = ADP + D-fructose 2,6-bisphosphate D-fructose 2,6-bisphosphate + H2O = 6-fructose 6-phosphate + Pi The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity [PUBMED:9652401]. The family described here bears a resemblance to the ATP-driven phospho-fructokinases, however, they share little sequence similarity, although a few residues seem key to their interaction with fructose 6-phosphate [PUBMED:9753654].

This domain forms the N-terminal region of this enzyme, while INTERPRO forms the C-terminal domain.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan P-loop_NTPase (CL0023), which has the following description:

AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].

The clan contains the following 229 members:

6PF2K AAA AAA-ATPase_like AAA_10 AAA_11 AAA_12 AAA_13 AAA_14 AAA_15 AAA_16 AAA_17 AAA_18 AAA_19 AAA_2 AAA_21 AAA_22 AAA_23 AAA_24 AAA_25 AAA_26 AAA_27 AAA_28 AAA_29 AAA_3 AAA_30 AAA_31 AAA_32 AAA_33 AAA_34 AAA_35 AAA_5 AAA_6 AAA_7 AAA_8 AAA_9 AAA_PrkA ABC_ATPase ABC_tran ABC_tran_Xtn Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arf ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 ATPase ATPase_2 Bac_DnaA BCA_ABC_TP_C Beta-Casp Cas_Csn2 Cas_St_Csn2 CbiA CBP_BcsQ CDC73_C CENP-M CFTR_R CLP1_P CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CSM2 CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DBINO DEAD DEAD_2 DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DUF1611 DUF1726 DUF2075 DUF2326 DUF2478 DUF257 DUF2791 DUF2813 DUF3584 DUF463 DUF815 DUF853 DUF87 DUF927 Dynamin_N Dynein_heavy Elong_Iki1 ELP6 ERCC3_RAD25_C Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GBP_C GTP_EFTU Gtr1_RagA Guanylate_kin GvpD HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD Herpes_Helicase Herpes_ori_bp Herpes_TK HSA HydF_dimer HydF_tetramer Hydin_ADK IIGP IPPT IPT IstB_IS21 KAP_NTPase KdpD Kinase-PPPase Kinesin KTI12 LAP1C Lon_2 LpxK MCM MeaB MEDS Mg_chelatase Microtub_bd MipZ MMR_HSR1 MMR_HSR1_C MobB MukB MutS_V Myosin_head NACHT NB-ARC NOG1 NTPase_1 NTPase_P4 ORC3_N ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Ploopntkinase1 Ploopntkinase2 Ploopntkinase3 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK PSY3 Rad17 Rad51 Ras RecA ResIII RHD3 RHSP RNA12 RNA_helicase Roc RsgA_GTPase RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2_N Spore_IV_A SRP54 SRPRB SulA Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulfotransfer_4 Sulphotransf SWI2_SNF2 T2SSE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6 Terminase_GpA Thymidylate_kin TIP49 TK TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind TsaE UvrB UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE Zeta_toxin Zot

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(11)
Full
(3821)
Representative proteomes UniProt
(5721)
NCBI
(8486)
Meta
(74)
RP15
(880)
RP35
(1838)
RP55
(2689)
RP75
(3366)
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HTML View  View               
PP/heatmap 1 View               

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(11)
Full
(3821)
Representative proteomes UniProt
(5721)
NCBI
(8486)
Meta
(74)
RP15
(880)
RP35
(1838)
RP55
(2689)
RP75
(3366)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(11)
Full
(3821)
Representative proteomes UniProt
(5721)
NCBI
(8486)
Meta
(74)
RP15
(880)
RP35
(1838)
RP55
(2689)
RP75
(3366)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_717 (release 4.1)
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 11
Number in full: 3821
Average length of the domain: 192.40 aa
Average identity of full alignment: 36 %
Average coverage of the sequence by the domain: 40.03 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.7 21.7
Trusted cut-off 21.7 21.7
Noise cut-off 21.6 21.6
Model length: 223
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Interactions

There are 3 interactions for this family. More...

His_Phos_1 6PF2K His_Phos_1

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the 6PF2K domain has been found. There are 27 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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