Phosphofructokinase 2 Explained

6-phosphofructo-2-kinase
Ec Number:2.7.1.105
Cas Number:78689-77-7
Go Code:0003873
Width:270
Symbol:6PF2K
6PF2K
Pfam:PF01591
Pfam Clan:CL0023
Interpro:IPR013079
Prosite:PDOC00158
Scop:1bif

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. 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] 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. 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.[3]

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.[4] One terminus serves as a kinase domain (for PFK-2) while the other terminus acts as a phosphatase domain (FBPase-2).[5]

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.[6]

Structure

The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N-terminal.[7] 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.[8] The PFK-2 domain appears to be closely related to the superfamily of mononucleotide binding proteins including adenylate cyclase.[9]

On the other hand, the phosphatase domain is located on the C-terminal.[10] It resembles the family of proteins that include phosphoglycerate mutases and acid phosphatases.[11] 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, the N-terminal region modulates PFK-2 and FBPase2 activities, and stabilizes the dimer form of the enzyme.[12]

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.[13] With some minor exceptions, the size of PFK-2 enzymes is typically around 55 kDa.

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.[14]

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.

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

ATP + beta-D-fructose 6-phosphate

\rightleftharpoons

ADP + beta-D-fructose 2,6-bisphosphate[15]

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.[16]

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

\rightleftharpoons

D-fructose 6-phosphate + phosphate[17]

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. On the other hand, the phosphatase reaction is characteristic of the family of hydrolases, specifically those acting on phosphoric monoester bonds.

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.[18]

Furthermore, the allosteric regulation of PFK2 is very similar to the regulation of PFK1.[19] 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.[20]

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.

Multiple mammalian isoforms of the protein have been reported to date, difference rising by either the transcription of different enzymes or alternative splicing.[21] [22] [23] 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. Because these areas often contain phosphorylation sites, changes in amino acid composition or terminal length may result in vastly different enzyme kinetics and characteristics. Each variant differs in their primary tissue of expression, response to protein kinase regulation, and ratio of kinase/phosphatase domain activity.[24] While multiple types of isozymes may consist in a tissue, isozymes are identified by their primary tissue expression and tissue of discovery below.

PFKB1: Liver, muscle, and fetal

6-phosphofructo-2-kinase: PFKB1
Ec Number:2.7.1.105
Cas Number:78689-77-7
Go Code:0003873
Width:180px
6-phosphofructo-2-kinase:PFKB1

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. Variable mRNA splicing of PFKB1 yields three different promoters (L, M and F) and therefore, three tissue-specific variants that differ in regulation:[25]

6-phosphofructo-2-kinase
Ec Number:2.7.1.105
Cas Number:78689-77-7
Go Code:0003873
Width:180px
6-phosphofructo-2-kinase:PFKB2

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.

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, glucagon 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.[37]

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. 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.[46] This isoform has been particularly implicated as being modified and hyper-expressed for prostate cancer cell survival.[47]

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. 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.[48] The control of PFK-2/FBP-ase2 activity was found to be linked to heart functioning, particularly for ischemia, and the control against hypoxia.[49] Researchers hypothesize that this responsive characteristic of the PFK-2 genes may be a strong, evolutionary physiological adaptation. 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.[50]

Lastly, the Pfkfb2 gene encoding PFK2/FBPase2 protein is linked to the predisposition to schizophrenia.[51]

References

External links

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

Notes and References

  1. Kurland IJ, Pilkis SJ . Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme . Protein Science . 4 . 6 . 1023–37 . June 1995 . 7549867 . 2143155 . 10.1002/pro.5560040601 .
  2. Lenzen S . A fresh view of glycolysis and glucokinase regulation: history and current status . The Journal of Biological Chemistry . 289 . 18 . 12189–94 . May 2014 . 24637025 . 4007419 . 10.1074/jbc.R114.557314 . free .
  3. Wang X, Deng Z, Kemp RG . An essential methionine residue involved in substrate binding by phosphofructokinases . Biochem. Biophys. Res. Commun. . 250 . 2 . 466–8 . September 1998 . 9753654 . 10.1006/bbrc.1998.9311 .
  4. Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L . 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 . August 2004 . 15170386 . 1133864 . 10.1042/BJ20040752 .
  5. Hasemann CA, Istvan ES, Uyeda K, Deisenhofer J . The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies . Structure . 4 . 9 . 1017–29 . September 1996 . 8805587 . 10.1016/S0969-2126(96)00109-8 . free .
  6. Atsumi T, Nishio T, Niwa H, Takeuchi J, Bando H, Shimizu C, Yoshioka N, Bucala R, Koike T . 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 . December 2005 . 16306349 . 10.2337/diabetes.54.12.3349 . free .
  7. Kurland I, Chapman B, Lee YH, Pilkis S . 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 . August 1995 . 7646523 . 10.1006/bbrc.1995.2183 .
  8. Walker JE, Saraste M, Runswick MJ, Gay NJ . 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 . 1982 . 6329717 . 553140 . 10.1002/j.1460-2075.1982.tb01276.x.
  9. Jedrzejas MJ . 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 . 2000 . 10958932 . 10.1016/S0079-6107(00)00007-9 . free .
  10. Li L, Lin K, Pilkis J, Correia JJ, Pilkis SJ . 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 . October 1992 . 10.1016/S0021-9258(19)36651-7 . 1328239 . free .
  11. Book: Stryer . Lubert . Berg . Jeremy Mark . Tymoczko . John L. . Biochemistry (Looseleaf) . W. H. Freeman . San Francisco . 2008 . The Balance Between Glycolysis and Gluconeogenesis in the Liver Is Sensitive to Blood-Glucose Concentration . 466–467 . 978-1-4292-3502-0 .
  12. Tominaga N, Minami Y, Sakakibara R, Uyeda K . 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 . July 1993 . 10.1016/S0021-9258(18)82344-4 . 8393455 . free .
  13. El-Maghrabi MR, Noto F, Wu N, Manes N . 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 . September 2001 . 11568503 . 10.1097/00075197-200109000-00012. 6638455 .
  14. Bazan JF, Fletterick RJ, Pilkis SJ . 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 . December 1989 . 2557623 . 298557 . 10.1073/pnas.86.24.9642. 1989PNAS...86.9642B . free .
  15. Web site: ENZYME entry 2.7.1.105 . enzyme.expasy.org . 2018-03-24 .
  16. Web site: 6-phosphofructo-2-kinase (IPR013079) . InterPro . EMBL-EBI . 2018-03-25 .
  17. Web site: ENZYME entry 3.1.3.46 . enzyme.expasy.org . 2018-03-25 .
  18. Okar DA, Manzano A, Navarro-Sabatè A, Riera L, Bartrons R, Lange AJ . PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate . Trends in Biochemical Sciences . 26 . 1 . 30–5 . January 2001 . 11165514 . 10.1016/S0968-0004(00)01699-6.
  19. Van Schaftingen E, Hers HG . 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 . August 1981 . 6458291 . 10.1016/0006-291X(81)91859-3 .
  20. Ros S, Schulze A . Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism . Cancer & Metabolism . 1 . 1 . 8 . February 2013 . 24280138 . 4178209 . 10.1186/2049-3002-1-8 . free .
  21. Darville MI, Crepin KM, Hue L, Rousseau GG . 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 . September 1989 . 2549541 . 297880 . 10.1073/pnas.86.17.6543 . 1989PNAS...86.6543D . free .
  22. Tsuchiya Y, Uyeda K . Bovine heart fructose 6-P,2-kinase:fructose 2,6-bisphosphatase mRNA and gene structure . Archives of Biochemistry and Biophysics . 310 . 2 . 467–74 . May 1994 . 8179334 . 10.1006/abbi.1994.1194 .
  23. Sakata J, Abe Y, Uyeda K . 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 . August 1991 . 10.1016/S0021-9258(18)98475-9 . 1651918 . free .
  24. 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. 10.1074/jbc.M113.455998. 3624444. 23457334. free.
  25. Book: Salway JG . Metabolism at a Glance . 978-0-470-67471-0 . Wiley-Blackwell . 2017 .
  26. Book: Hue L, Rider MH, Rousseau GG . Fructose-2,6-bisphosphate in extra hepatic tissues . 173–193 . Pilkis SJ . Fructose-2,6-bisphosphate . 1990 . CRC Press . Boca Raton, Fla. . 978-0-8493-4795-5 .
  27. Pilkis SJ, el-Maghrabi MR, Claus TH . Hormonal regulation of hepatic gluconeogenesis and glycolysis . Annual Review of Biochemistry . 57 . 755–83 . 1988 . 3052289 . 10.1146/annurev.bi.57.070188.003543 .
  28. Marker AJ, Colosia AD, Tauler A, Solomon DH, Cayre Y, Lange AJ, el-Maghrabi MR, Pilkis SJ . Glucocorticoid regulation of hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression . The Journal of Biological Chemistry . 264 . 12 . 7000–4 . April 1989 . 10.1016/S0021-9258(18)83531-1 . 2540168 . free .
  29. Cosin-Roger J, Vernia S, Alvarez MS, Cucarella C, Boscá L, Martin-Sanz P, Fernández-Alvarez AJ, Casado M . Identification of a novel Pfkfb1 mRNA variant in rat fetal liver . Biochemical and Biophysical Research Communications . 431 . 1 . 36–40 . February 2013 . 23291237 . 10.1016/j.bbrc.2012.12.109 . 11336/19538 . free .
  30. Darville MI, Chikri M, Lebeau E, Hue L, Rousseau GG . A rat gene encoding heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase . FEBS Letters . 288 . 1–2 . 91–4 . August 1991 . 1652483 . 10.1016/0014-5793(91)81009-W. 34116121 . free .
  31. Heine-Suñer D, Díaz-Guillén MA, Lange AJ, Rodríguez de Córdoba S . 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 . May 1998 . 9652401 . 10.1046/j.1432-1327.1998.2540103.x. free .
  32. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L . 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 . October 2000 . 11069105 . 10.1016/S0960-9822(00)00742-9. 7920767 . free . 2000CBio...10.1247M .
  33. Navarro-Sabaté A, Manzano A, Riera L, Rosa JL, Ventura F, Bartrons R . The human ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene (PFKFB3): promoter characterization and genomic structure . Gene . 264 . 1 . 131–8 . February 2001 . 11245987 . 10.1016/S0378-1119(00)00591-6 .
  34. Riera L, Manzano A, Navarro-Sabaté A, Perales JC, Bartrons R . Insulin induces PFKFB3 gene expression in HT29 human colon adenocarcinoma cells . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1589 . 2 . 89–92 . April 2002 . 12007784 . 10.1016/S0167-4889(02)00169-6 . free .
  35. Marsin AS, Bouzin C, Bertrand L, Hue L . 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 . August 2002 . 12065600 . 10.1074/jbc.M205213200 . free .
  36. Sakakibara R, Kato M, Okamura N, Nakagawa T, Komada Y, Tominaga N, Shimojo M, Fukasawa M . Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase . Journal of Biochemistry . 122 . 1 . 122–8 . July 1997 . 9276680 . 10.1093/oxfordjournals.jbchem.a021719.
  37. Manes NP, El-Maghrabi MR . 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 . June 2005 . 15896703 . 10.1016/j.abb.2005.04.011 .
  38. Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y, Han JH, Metz C, Bucala R . 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 . March 1999 . 10077634 . 15892 . 10.1073/pnas.96.6.3047. 1999PNAS...96.3047C . free .
  39. Manzano A, Rosa JL, Ventura F, Pérez JX, Nadal M, Estivill X, Ambrosio S, Gil J, Bartrons R . 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 . 1998 . 10072580 . 10.1159/000015181 . 23221556 .
  40. Sakai A, Kato M, Fukasawa M, Ishiguro M, Furuya E, Sakakibara R . 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 . March 1996 . 8830046 . 10.1093/oxfordjournals.jbchem.a021270.
  41. Ventura F, Ambrosio S, Bartrons R, el-Maghrabi MR, Lange AJ, Pilkis SJ . 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 . April 1995 . 7733968 . 10.1006/bbrc.1995.1616.
  42. Bando H, Atsumi T, Nishio T, Niwa H, Mishima S, Shimizu C, Yoshioka N, Bucala R, Koike T . 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 . August 2005 . 16115917 . 10.1158/1078-0432.CCR-05-0149 . free .
  43. Riera L, Obach M, Navarro-Sabaté A, Duran J, Perales JC, Viñals F, Rosa JL, Ventura F, Bartrons R . 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 . August 2003 . 12935880 . 10.1016/S0014-5793(03)00808-1. 41726316 . free .
  44. Ventura F, Rosa JL, Ambrosio S, Pilkis SJ, Bartrons R . 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 . September 1992 . 10.1016/S0021-9258(19)37133-9 . 1325453 . free . 2445/177133 . free .
  45. Manzano A, Pérez JX, Nadal M, Estivill X, Lange A, Bartrons R . Cloning, expression and chromosomal localization of a human testis 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene . Gene . 229 . 1–2 . 83–9 . March 1999 . 10095107 . 10.1016/S0378-1119(99)00037-2.
  46. Gómez M, Manzano A, Navarro-Sabaté A, Duran J, Obach M, Perales JC, Bartrons R . Specific expression of pfkfb4 gene in spermatogonia germ cells and analysis of its 5'-flanking region . FEBS Letters . 579 . 2 . 357–62 . January 2005 . 15642344 . 10.1016/j.febslet.2004.11.096 . 33170865 .
  47. Ros S, Santos CR, Moco S, Baenke F, Kelly G, Howell M, Zamboni N, Schulze A . 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 . April 2012 . 22576210 . 10.1158/2159-8290.CD-11-0234 . free .
  48. 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.
  49. Wang Q, Donthi RV, Wang J, Lange AJ, Watson LJ, Jones SP, Epstein PN . 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 . June 2008 . 18456722 . 10.1152/ajpheart.91501.2007 . 4239994 .
  50. Minchenko OH, Opentanova IL, Ogura T, Minchenko DO, Komisarenko SV, Caro J, Esumi H . 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 . 2005 . 16025159 . 10.18388/abp.2005_3402. free .
  51. Stone WS, Faraone SV, Su J, Tarbox SI, Van Eerdewegh P, Tsuang MT . 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 . May 2004 . 15108172 . 10.1002/ajmg.b.20132 . 2420843 . free .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Phosphofructokinase 2".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.