Phosphofructokinase 2: Difference between revisions

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{{enzyme
| Name = 6-phosphofructo-2-kinase
| EC_number = 2.7.1.105
| CAS_number = 78689-77-7
| IUBMB_EC_number = 2/7/1/105
| GO_code = 0003873
| image =
| width =
| caption =
}}
{{enzyme
| Name = fructose-2,6-bisphosphate 2-phosphatase
| EC_number = 3.1.3.46
| CAS_number = 81611-75-8
| IUBMB_EC_number = 3/1/3/46
| GO_code = 0004331
| image =
| width =
| caption =
}}
{{Pfam_box  
{{Pfam_box  
| Symbol = 6PF2K  
| Symbol = 6PF2K  
| Name = 6-phosphofructo-2-kinase  
| Name = 6-phosphofructo-2-kinase/fructose-bisphosphatase-2
| image = Phosphofructokinase 2.jpg
| image = Phosphofructokinase 2.jpg
| width =  
| width =  
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| OPM protein=  
| OPM protein=  
| PDB=  
| PDB=  
{{PDB2|2axn}} A:24-246; {{PDB2|1k6m}} B:40-251; {{PDB2|2bif}} A:30-249; {{PDB2|3bif}} A:30-249; {{PDB2|1bif}} :37-249  
{{PDB2|2axn}} A:24-246; {{PDB2|1k6m}} B:40-251; {{PDB2|2bif}} A:30-249; {{PDB2|3bif}} A:30-249; {{PDB2|1bif}} :37-249
}}  
}}
{{Pfam_box
| Symbol = FBPase-2
| Name = fructose-bisphosphatase-2
| Pfam= PF00316
| InterPro= IPR028343
| SMART=
| Prosite = PDOC00114
| SCOP =
| TCDB =
| OPM family=
| OPM protein=
| PDB=
}}


'''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.<ref name="pmid1339450">{{cite journal | vauthors = Kurland IJ, el-Maghrabi MR, Correia JJ, Pilkis SJ | title = Rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Properties of phospho- and dephospho- forms and of two mutants in which Ser32 has been changed by site-directed mutagenesis | journal = J. Biol. Chem. | volume = 267 | issue = 7 | pages = 4416–23 |date=March 1992 | pmid = 1339450 | doi = | url = }}</ref> 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 mutase]]s.  
'''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|fructose-2,6-bisphosphate]] (Fru-2,6-P<sub>2</sub>) from substrate [[Fructose 6-phosphate|fructose-6-phosphate]]. Fru-2,6-P<sub>2</sub> contributes to the rate-determining step of glycolysis as it activates enzyme [[Phosphofructokinase 1]] in the glycolysis pathway, and inhibits [[Fructose 1,6-bisphosphatase|fructose-1,6-bisphosphatase 1]] in gluconeogenesis.<ref name="Kurland_1995">{{cite journal | vauthors = Kurland IJ, Pilkis SJ | title = Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme | journal = Protein Science | volume = 4 | issue = 6 | pages = 1023–37 | date = June 1995 | pmid = 7549867 | pmc = 2143155 | doi = 10.1002/pro.5560040601 }}</ref> Since Fru-2,6-P<sub>2</sub> differentially regulates glycolysis and gluconeogenesis, it can act as a key signal to switch between the opposing pathways.<ref name="Kurland_1995" /> Because PFK-2 produces Fru-2,6-P<sub>2</sub> in response to hormonal signaling, [[metabolism]] can be more sensitively and efficiently controlled to align with the organism's glycolytic needs.<ref name="pmid24637025">{{cite journal | vauthors = Lenzen S | title = A fresh view of glycolysis and glucokinase regulation: history and current status | journal = The Journal of Biological Chemistry | volume = 289 | issue = 18 | pages = 12189–94 | date = May 2014 | pmid = 24637025 | pmc = 4007419 | doi = 10.1074/jbc.R114.557314 }}</ref>


==Structure==
PFK-2 is known as the "bifunctional enzyme" because of its notable structure: though both are located on one protein [[Protein dimer|homodimer]], its two domains act as independently functioning enzymes.<ref name="Rider_2004">{{cite journal | vauthors = Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L | title = 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis | journal = The Biochemical Journal | volume = 381 | issue = Pt 3 | pages = 561–79 | date = August 2004 | pmid = 15170386 | pmc = 1133864 | doi = 10.1042/BJ20040752 }}</ref> One terminus serves as a [[kinase]] domain (for PFK-2) while the other terminus acts as a [[phosphatase]] domain (FBPase-2).<ref name="Hasemann_1996">{{cite journal | vauthors = Hasemann CA, Istvan ES, Uyeda K, Deisenhofer J | title = The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies | journal = Structure | volume = 4 | issue = 9 | pages = 1017–29 | date = September 1996 | pmid = 8805587 | doi =10.1016/S0969-2126(96)00109-8 }}</ref>
The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N-terminal.<ref name="pmid7646523">{{cite journal | vauthors = Kurland I, Chapman B, Lee YH, Pilkis S | title = Evolutionary reengineering of the phosphofructokinase active site: ARG-104 does not stabilize the transition state in 6-phosphofructo-2-kinase | journal = Biochem. Biophys. Res. Commun. | volume = 213 | issue = 2 | pages = 663–72 |date=August 1995 | pmid = 7646523 | doi = 10.1006/bbrc.1995.2183 | url =  }}</ref> It consists of a central six-stranded β sheet, with five parallel strands and an antiparallel edge strand, surrounded by seven α helices.<ref name="Hasemann_1996">{{cite journal | vauthors = Hasemann CA, Istvan ES, Uyeda K, Deisenhofer J | title = The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies | journal = Structure | volume = 4 | issue = 9 | pages = 1017–29 |date=September 1996 | pmid = 8805587 | doi = 10.1016/S0969-2126(96)00109-8| url =  }}</ref> The domain contains nucleotide-binding fold (nbf) at the C-terminal end of the first β-strand,<ref name="pmid6329717">{{cite journal | vauthors = Walker JE, Saraste M, Runswick MJ, Gay NJ | title = 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 | journal = EMBO J. | volume = 1 | issue = 8 | pages = 945–51 | year = 1982 | pmid = 6329717 | pmc = 553140 | doi = | url =  }}</ref> and thus resembles the structure of adenylate kinase. 


On the other hand, the phosphatase domain is located on the C-terminal.<ref name="pmid1328239">{{cite journal | vauthors = Li L, Lin K, Pilkis J, Correia JJ, Pilkis SJ | title = 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 | journal = J. Biol. Chem. | volume = 267 | issue = 30 | pages = 21588–94 |date=October 1992 | pmid = 1328239 | doi = | url =  }}</ref> It resembles the family of proteins that include phosphoglycerate mutases (PGMs) and acid phosphatases.<ref name="Stryer_2008">{{cite book | author1 = Stryer, Lubert |author2 = Berg, Jeremy Mark|author3 = Tymoczko, John L. | authorlink = | editor = | others = | title = Biochemistry (Looseleaf) | edition = | language = | publisher = W. H. Freeman | location = San Francisco | year = 2008 | chapter =The Balance Between Glycolysis and Gluconeogenesis in the Liver Is Sensitive to Blood-Glucose Concentration  | pages =  466–467 | quote = | isbn = 1-4292-3502-0 | oclc = | doi = | url = | accessdate = }}</ref> 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.<ref name="Hasemann_1996"/> Finally, N-terminal region modulates PFK2 and FBPase2 activities, and stabilizes the dimer form of the enzyme.<ref name="Stryer_2008"/><ref name="pmid8393455">{{cite journal | vauthors = Tominaga N, Minami Y, Sakakibara R, Uyeda K | title = Significance of the amino terminus of rat testis fructose-6-phosphate, 2-kinase:fructose-2,6-bisphosphatase | journal = J. Biol. Chem. | volume = 268 | issue = 21 | pages = 15951–7 |date=July 1993 | pmid = 8393455 | doi = | url =  }}</ref>
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.<ref name="pmid16306349">{{cite journal | vauthors = Atsumi T, Nishio T, Niwa H, Takeuchi J, Bando H, Shimizu C, Yoshioka N, Bucala R, Koike T | title = Expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase/PFKFB3 isoforms in adipocytes and their potential role in glycolytic regulation | journal = Diabetes | volume = 54 | issue = 12 | pages = 3349–57 | date = December 2005 | pmid = 16306349 | doi = 10.2337/diabetes.54.12.3349 }}</ref>


==Function==
== Structure ==
When glucose level is low, glucagon is released into the bloodstream, triggering a [[cAMP-dependent pathway|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.<ref name="pmid7574501">{{cite journal | vauthors = Pilkis SJ, Claus TH, Kurland IJ, Lange AJ | title = 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: a metabolic signaling enzyme | journal = Annu. Rev. Biochem. | volume = 64 | issue = | pages = 799–835 | year = 1995 | pmid = 7574501 | doi = 10.1146/annurev.bi.64.070195.004055 | url =  }}</ref>
The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N-terminal.<ref name="pmid7646523">{{cite journal | vauthors = Kurland I, Chapman B, Lee YH, Pilkis S | title = Evolutionary reengineering of the phosphofructokinase active site: ARG-104 does not stabilize the transition state in 6-phosphofructo-2-kinase | journal = Biochemical and Biophysical Research Communications | volume = 213 | issue = 2 | pages = 663–72 | date = August 1995 | pmid = 7646523 | doi = 10.1006/bbrc.1995.2183 }}</ref> It consists of a central six-stranded β sheet, with five parallel strands and an antiparallel edge strand, surrounded by seven α helices.<ref name="Hasemann_1996" /> The domain contains nucleotide-binding fold (nbf) at the C-terminal end of the first β-strand.<ref name="pmid6329717">{{cite journal | vauthors = Walker JE, Saraste M, Runswick MJ, Gay NJ | title = 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 | journal = The EMBO Journal | volume = 1 | issue = 8 | pages = 945–51 | year = 1982 | pmid = 6329717 | pmc = 553140 | doi =  }}</ref> The PFK-2 domain appears to be closely related to the superfamily of mononucleotide binding proteins including [[adenylate cyclase]].<ref name="Jedrzejas_2000">{{cite journal | vauthors = Jedrzejas MJ | title = Structure, function, and evolution of phosphoglycerate mutases: comparison with fructose-2,6-bisphosphatase, acid phosphatase, and alkaline phosphatase | journal = Progress in Biophysics and Molecular Biology | volume = 73 | issue = 2-4 | pages = 263–87 | date = 2000 | pmid = 10958932 | doi = 10.1016/S0079-6107(00)00007-9 }}</ref>


On the other hand, when the glucose level increases, the level of [[fructose 6-phosphate]] (F6P) subsequently rises and the molecule stimulates [[PPP1R1B|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.
On the other hand, the phosphatase domain is located on the C-terminal.<ref name="pmid1328239">{{cite journal | vauthors = Li L, Lin K, Pilkis J, Correia JJ, Pilkis SJ | title = 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 | journal = The Journal of Biological Chemistry | volume = 267 | issue = 30 | pages = 21588–94 | date = October 1992 | pmid = 1328239 | doi =  }}</ref> It resembles the family of proteins that include phosphoglycerate mutases and acid phosphatases.<ref name="Jedrzejas_2000" /><ref name="Stryer_2008">{{cite book | last1 = Stryer | first1 = Lubert | last2 = Berg | first2 = Jeremy Mark | last3 = Tymoczko | first3 = John L. |name-list-format = vanc | title = Biochemistry (Looseleaf) | edition = | publisher = W. H. Freeman | location = San Francisco | year = 2008 | chapter = The Balance Between Glycolysis and Gluconeogenesis in the Liver Is Sensitive to Blood-Glucose Concentration  | pages =  466–467 | isbn = 978-1-4292-3502-0 }}</ref> 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.<ref name="Hasemann_1996" /> Finally, the N-terminal region modulates PFK-2 and FBPase2 activities, and stabilizes the dimer form of the enzyme.<ref name="Stryer_2008" /><ref name="Tominaga_1993">{{cite journal | vauthors = Tominaga N, Minami Y, Sakakibara R, Uyeda K | title = Significance of the amino terminus of rat testis fructose-6-phosphate, 2-kinase:fructose-2,6-bisphosphatase | journal = The Journal of Biological Chemistry | volume = 268 | issue = 21 | pages = 15951–7 | date = July 1993 | pmid = 8393455 | doi =  }}</ref>


==Regulation==
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.<ref name="El-Maghrabi_2001">{{cite journal | vauthors = El-Maghrabi MR, Noto F, Wu N, Manes N | title = 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: suiting structure to need, in a family of tissue-specific enzymes | journal = Current Opinion in Clinical Nutrition and Metabolic Care | volume = 4 | issue = 5 | pages = 411–8 | date = September 2001 | pmid = 11568503 | doi = }}</ref> With some minor exceptions, the size of PFK-2 enzymes is typically around 55 kDa.<ref name="Kurland_1995" />
The allosteric regulation of PFK2 is very similar to the regulation of [[PFK1]].<ref name="Van Schaftingen_1981">{{cite journal | vauthors = Van Schaftingen E, Hers HG | title = Phosphofructokinase 2: the enzyme that forms fructose 2,6-bisphosphate from fructose 6-phosphate and ATP | journal = Biochem. Biophys. Res. Commun. | volume = 101 | issue = 3 | pages = 1078–84 |date=August 1981 | pmid = 6458291 | doi = 10.1016/0006-291X(81)91859-3| url =  }}</ref> High levels of [[Adenosine monophosphate|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
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.<ref name="pmid2557623">{{cite journal | vauthors = Bazan JF, Fletterick RJ, Pilkis SJ | title = Evolution of a bifunctional enzyme: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 24 | pages = 9642–6 | date = December 1989 | pmid = 2557623 | pmc = 298557 | doi = }}</ref>


== Reaction mechanism ==
== Function ==
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.<ref name="Van Schaftingen_1981"/>
This enzyme's main function is to synthesize or degrade allosteric regulator Fru-2,6-P<sub>2</sub> in response to glycolytic needs of the cell or organism, as depicted in the accompanying diagram.[[File:PFK-2-FBP-ase 2 Reaction.png|left|thumb|300x300px|PFK-2 and FBPase-2 Reaction]]


<!-- [[File:FBPase2 mechanism.gif|thumb|400px|FBPase2 hydrolyzes F-2,6-BP into F6P and phosphate]] -->
In [[enzymology]], a 6-phosphofructo-2-kinase ({{EC number|2.7.1.105}}) is an [[enzyme]] that [[catalysis|catalyzes]] the [[chemical reaction]]:
The hydrolysis of fructose 2,6-biphosphate is likely to follow the below steps:<ref name="pmid1313012">{{cite journal | vauthors = Lin K, Li L, Correia JJ, Pilkis SJ | title = Glu327 is part of a catalytic triad in rat liver fructose-2,6-bisphosphatase | journal = J. Biol. Chem. | volume = 267 | issue = 10 | pages = 6556–62 |date=April 1992 | pmid = 1313012 | doi = | url =  }}</ref>


# Histidine acts as a nucleophile and attacks the 2-phosphate of F-2,6-BP
:ATP + beta-D-fructose 6-phosphate <math>\rightleftharpoons</math> ADP + beta-D-fructose 2,6-bisphosphate<ref name=":0">{{cite web | url = https://enzyme.expasy.org/EC/2.7.1.105 | title = ENZYME entry 2.7.1.105 | website = enzyme.expasy.org | access-date = 2018-03-24 }}</ref>
#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 ==
Thus, the kinase domain hydrolyzes ATP to phosphorylate the carbon-2 of fructose-6-phosphate, producing Fru-2,6-P<sub>2</sub> and ADP<sub>.</sub> A phosphohistidine intermediate is formed within the reaction.<ref>{{cite web | url = https://www.ebi.ac.uk/interpro/entry/IPR013079|title=6-phosphofructo-2-kinase (IPR013079) | work = InterPro | publisher = EMBL-EBI | access-date = 2018-03-25 }}</ref>
The ''Pfkfb2'' gene encoding PFK2/FBPase2 protein is linked to the predisposition to [[schizophrenia]].<ref name="pmid15108172">{{cite journal | vauthors = Stone WS, Faraone SV, Su J, Tarbox SI, Van Eerdewegh P, Tsuang MT | title = Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample | journal = Am. J. Med. Genet. B Neuropsychiatr. Genet. | volume = 127B | issue = 1 | pages = 5–10 |date=May 2004 | pmid = 15108172 | doi = 10.1002/ajmg.b.20132 | url =  }}</ref> Furthermore, the control of PFK2/FBPase2 activity was found to be linked to heart functioning and the control against [[hypoxia (medical)|hypoxia]].<ref name="pmid18456722">{{cite journal | vauthors = Wang Q, Donthi RV, Wang J, Lange AJ, Watson LJ, Jones SP, Epstein PN | title = Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia | journal = Am. J. Physiol. Heart Circ. Physiol. | volume = 294 | issue = 6 | pages = H2889–97 |date=June 2008 | pmid = 18456722 | doi = 10.1152/ajpheart.91501.2007 | url =  }}</ref>
 
:At the other terminal, the fructose-2,6-bisphosphate 2-phosphatase ([[Enzyme Commission number|EC]] [https://enzyme.expasy.org/EC/3.1.3.46 3.1.3.46]) domain dephosphorylates Fru-2,6-P<sub>2</sub> with the addition of water. This opposing chemical reaction is:
:beta-D-fructose 2,6-bisphosphate + H<sub>2</sub>O <math>\rightleftharpoons</math>  D-fructose 6-phosphate + phosphate<ref name=":1">{{cite web | url = https://enzyme.expasy.org/EC/3.1.3.46 | title = ENZYME entry 3.1.3.46 | website = enzyme.expasy.org | access-date = 2018-03-25 }}</ref>
:
 
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 [[transferase]]s, specifically those transferring phosphorus-containing groups ([[phosphotransferase]]s) with an alcohol group as acceptor.<ref name=":0" /> On the other hand, the phosphatase reaction is characteristic of the family of [[hydrolase]]s, specifically those acting on phosphoric [[Ester|monoester]] bonds.<ref name=":1" />
 
== 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-P<sub>2</sub> will be synthesized or degraded.<ref name="Okar_2001">{{cite journal | vauthors = Okar DA, Manzano A, Navarro-Sabatè A, Riera L, Bartrons R, Lange AJ | title = PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate | journal = Trends in Biochemical Sciences | volume = 26 | issue = 1 | pages = 30–5 | date = January 2001 | pmid = 11165514 | doi = }}</ref>
 
Furthermore, the allosteric regulation of PFK2 is very similar to the regulation of [[PFK1]].<ref name="Van Schaftingen_1981">{{cite journal | vauthors = Van Schaftingen E, Hers HG | title = Phosphofructokinase 2: the enzyme that forms fructose 2,6-bisphosphate from fructose 6-phosphate and ATP | journal = Biochemical and Biophysical Research Communications | volume = 101 | issue = 3 | pages = 1078–84 | date = August 1981 | pmid = 6458291 | doi = 10.1016/0006-291X(81)91859-3 }}</ref> High levels of [[Adenosine monophosphate|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.<ref name="pmid24280138">{{cite journal | vauthors = Ros S, Schulze A | title = Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism | journal = Cancer & Metabolism | volume = 1 | issue = 1 | pages = 8 | date = February 2013 | pmid = 24280138 | pmc = 4178209 | doi = 10.1186/2049-3002-1-8 }}</ref>
#


== Isozymes ==
== Isozymes ==
Five mammalian isozymes of the protein have been reported to date, difference rising by either the transcription of different enzymes or alternative splicing.<ref name="pmid2549541">{{cite journal | vauthors = Darville MI, Crepin KM, Hue L, Rousseau GG | title = 5' flanking sequence and structure of a gene encoding rat 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 86 | issue = 17 | pages = 6543–7 |date=September 1989 | pmid = 2549541 | pmc = 297880 | doi = 10.1073/pnas.86.17.6543| url =  }}</ref><ref name="pmid8179334">{{cite journal | vauthors = Tsuchiya Y, Uyeda K | title = Bovine heart fructose 6-P,2-kinase:fructose 2,6-bisphosphatase mRNA and gene structure | journal = Arch. Biochem. Biophys. | volume = 310 | issue = 2 | pages = 467–74 |date=May 1994 | pmid = 8179334 | doi = 10.1006/abbi.1994.1194| url =  }}</ref><ref name="pmid1651918">{{cite journal | vauthors = Sakata J, Abe Y, Uyeda K | title = Molecular cloning of the DNA and expression and characterization of rat testes fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase | journal = J. Biol. Chem. | volume = 266 | issue = 24 | pages = 15764–70 |date=August 1991 | pmid = 1651918 | doi = | url = }}</ref>The isozymes differ radically in their regulation and the discussions above are based on liver isozyme.<ref name="Hasemann_1996"/>
Protein [[isozyme]]s 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 [[PFKFB1|PFKFB-1]], [[PFKFB2]], [[PFKFB3]] and [[PFKFB4]].<ref name="Rider_2004" />
 
Multiple mammalian isoforms of the protein have been reported to date, difference rising by either the transcription of different enzymes or alternative splicing.<ref name="pmid2549541">{{cite journal | vauthors = Darville MI, Crepin KM, Hue L, Rousseau GG | title = 5' flanking sequence and structure of a gene encoding rat 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 17 | pages = 6543–7 | date = September 1989 | pmid = 2549541 | pmc = 297880 | doi = 10.1073/pnas.86.17.6543 }}</ref><ref name="pmid8179334">{{cite journal | vauthors = Tsuchiya Y, Uyeda K | title = Bovine heart fructose 6-P,2-kinase:fructose 2,6-bisphosphatase mRNA and gene structure | journal = Archives of Biochemistry and Biophysics | volume = 310 | issue = 2 | pages = 467–74 | date = May 1994 | pmid = 8179334 | doi = 10.1006/abbi.1994.1194 }}</ref><ref name="pmid1651918">{{cite journal | vauthors = Sakata J, Abe Y, Uyeda K | title = Molecular cloning of the DNA and expression and characterization of rat testes fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase | journal = The Journal of Biological Chemistry | volume = 266 | issue = 24 | pages = 15764–70 | date = August 1991 | pmid = 1651918 | doi = }}</ref> 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.<ref name="El-Maghrabi_2001" /> Because these areas often contain phosphorylation sites, changes in amino acid composition or terminal length may result in vastly different enzyme kinetics and characteristics.<ref name="Kurland_1995" /><ref name="El-Maghrabi_2001" /> Each variant differs in their primary tissue of expression, response to protein kinase regulation, and ratio of kinase/phosphatase domain activity.<ref name="Novellasdemunt_2013">{{cite journal|vauthors=Novellasdemunt L, Tato I, Navarro-Sabate A, Ruiz-Meana M, Méndez-Lucas A, Perales JC, Garcia-Dorado D, Ventura F, Bartrons R, Rosa JL|date=April 2013|title=Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids|journal=The Journal of Biological Chemistry|volume=288|issue=15|pages=10640–51|doi=10.1074/jbc.M113.455998|pmc=3624444|pmid=23457334}}</ref> While multiple types of isozymes may consist in a tissue, isozymes are identified by their primary tissue expression and tissue of discovery below.<ref name="Gómez_2005" />
 
=== PFKB1: Liver, muscle, and fetal ===
 
{{enzyme
| Name = 6-phosphofructo-2-kinase: PFKB1
| EC_number = 2.7.1.105
| CAS_number = 78689-77-7
| IUBMB_EC_number = 2/7/1/105
| GO_code = 0003873
| image = PDB 1k6m EBI.jpg
| width = 180px
| caption = Crystal structure of human liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
|name=6-phosophofructo-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.<ref name="pmid2549541" /> Variable mRNA splicing of PFKB1 yields three different promoters (L, M and F) and therefore, three tissue-specific variants that differ in regulation:<ref name = "Salway_2017">{{cite book | vauthors = Salway JG | title = Metabolism at a Glance | isbn = 978-0-470-67471-0 | publisher = Wiley-Blackwell | year = 2017 }}</ref>
* 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-P<sub>2.</sub> As this product allosterically activates PFK-1, it activates glycolysis and inhibits gluconeogenesis.<ref>{{cite book | vauthors = Hue L, Rider MH, Rousseau GG | chapter = Fructose-2,6-bisphosphate in extra hepatic tissues | pages = 173–193 | veditors = Pilkis SJ | title = Fructose-2,6-bisphosphate | date = 1990 | publisher = CRC Press | location = Boca Raton, Fla. | isbn = 978-0-8493-4795-5 }}</ref>
** In contrast, [[glucagon]] increases FBPase-2 activity. At low blood glucose concentrations, glucagon triggers a [[Cyclic adenosine monophosphate|cAMP signal cascade]] and in turn, [[Protein kinase A|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-P<sub>2,</sub> slows rates of glycolysis, and stimulates the gluconeogenesis pathway.<ref name="pmid3052289">{{cite journal | vauthors = Pilkis SJ, el-Maghrabi MR, Claus TH | title = Hormonal regulation of hepatic gluconeogenesis and glycolysis | journal = Annual Review of Biochemistry | volume = 57 | issue = | pages = 755–83 | date = 1988 | pmid = 3052289 | doi = 10.1146/annurev.bi.57.070188.003543 }}</ref><ref name="Marker_1989">{{cite journal | vauthors = Marker AJ, Colosia AD, Tauler A, Solomon DH, Cayre Y, Lange AJ, el-Maghrabi MR, Pilkis SJ | title = Glucocorticoid regulation of hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression | journal = The Journal of Biological Chemistry | volume = 264 | issue = 12 | pages = 7000–4 | date = April 1989 | pmid = 2540168 | doi = }}</ref>
[[File:Liver Tissue PFK-2 Regulation.png|center|thumb|714x714px|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<ref name="Cosin-Roger_2013">{{cite journal | vauthors = Cosin-Roger J, Vernia S, Alvarez MS, Cucarella C, Boscá L, Martin-Sanz P, Fernández-Alvarez AJ, Casado M | title = Identification of a novel Pfkfb1 mRNA variant in rat fetal liver | journal = Biochemical and Biophysical Research Communications | volume = 431 | issue = 1 | pages = 36–40 | date = February 2013 | pmid = 23291237 | doi = 10.1016/j.bbrc.2012.12.109 }}</ref>
** 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.<ref name="Salway_2017" />
{{enzyme
| Name = 6-phosphofructo-2-kinase
| EC_number = 2.7.1.105
| CAS_number = 78689-77-7
| IUBMB_EC_number = 2/7/1/105
| GO_code = 0003873
| image = 5htk.jpg
| width = 180px
| caption = 6-phosphofructo-2-kinase dimer, Human heart tissue
|name=6-phosophofructo-2-kinase:
PFKB2}}


Humans genes encoding proteins possessing phosphofructokinase 2 activity include:
=== PFKB2: Cardiac (H-Type) ===
* [[PFKFB1]], [[PFKFB2]], [[PFKFB3]], [[PFKFB4]]
The PFKB2 gene is located on chromosome 1.<ref name="pmid1652483">{{cite journal | vauthors = Darville MI, Chikri M, Lebeau E, Hue L, Rousseau GG | title = A rat gene encoding heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase | journal = FEBS Letters | volume = 288 | issue = 1-2 | pages = 91–4 | date = August 1991 | pmid = 1652483 | doi = }}</ref> 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.<ref name="pmid9652401">{{cite journal | vauthors = Heine-Suñer D, Díaz-Guillén MA, Lange AJ, Rodríguez de Córdoba S | title = Sequence and structure of the human 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase heart isoform gene (PFKFB2) | journal = European Journal of Biochemistry | volume = 254 | issue = 1 | pages = 103–10 | date = May 1998 | pmid = 9652401 | doi = }}</ref> Alternatively, [[Protein kinase B|Protein Kinase B]] may also phosphorylate these regulatory sites, which are part of the FBPase-2 domain.<ref name="pmid11069105">{{cite journal | vauthors = Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L | title = Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia | journal = Current Biology | volume = 10 | issue = 20 | pages = 1247–55 | date = October 2000 | pmid = 11069105 | doi = }}</ref> When this serine residue is phosphorylated, FBPase-2 function is inactivated and greater PFK-2 activity is stabilized.<ref name="Salway_2017" />


==References==
=== PFKB3: Brain, placental, and inducible ===
{{reflist}}
PFKB3 is located on chromosome 10 and transcribes two major isoforms, inducible type and ubiquitous type.<ref name="Navarro-Sabaté_2001">{{cite journal | vauthors = Navarro-Sabaté A, Manzano A, Riera L, Rosa JL, Ventura F, Bartrons R | title = The human ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene (PFKFB3): promoter characterization and genomic structure | journal = Gene | volume = 264 | issue = 1 | pages = 131–8 | date = February 2001 | pmid = 11245987 | doi =  10.1016/S0378-1119(00)00591-6 }}</ref> These forms differ in alternative splicing of Exon 15 in their C-terminus.<ref name="pmid12007784">{{cite journal | vauthors = Riera L, Manzano A, Navarro-Sabaté A, Perales JC, Bartrons R | title = Insulin induces PFKFB3 gene expression in HT29 human colon adenocarcinoma cells | journal = Biochimica et Biophysica Acta | volume = 1589 | issue = 2 | pages = 89–92 | date = April 2002 | pmid = 12007784 | doi = 10.1016/S0167-4889(02)00169-6 }}</ref> 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.<ref name="Marsin+2002">{{cite journal | vauthors = Marsin AS, Bouzin C, Bertrand L, Hue L | title = The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 30778–83 | date = August 2002 | pmid = 12065600 | doi = 10.1074/jbc.M205213200 }}</ref> 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).<ref name="Sakakibara_1997">{{cite journal | vauthors = Sakakibara R, Kato M, Okamura N, Nakagawa T, Komada Y, Tominaga N, Shimojo M, Fukasawa M | title = Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase | journal = Journal of Biochemistry | volume = 122 | issue = 1 | pages = 122–8 | date = July 1997 | pmid = 9276680 | doi = | url = https://www.jstage.jst.go.jp/article/biochemistry1922/122/1/122_1_122/_article }}</ref> Therefore, PFKB3 in particular consistently produces large amounts of F-2,6-P<sub>2</sub> and sustains high rates of glycolysis.<ref name="Sakakibara_1997" /><ref name="Manes_2005">{{cite journal | vauthors = Manes NP, El-Maghrabi MR | title = The kinase activity of human brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is regulated via inhibition by phosphoenolpyruvate | journal = Archives of Biochemistry and Biophysics | volume = 438 | issue = 2 | pages = 125–36 | date = June 2005 | pmid = 15896703 | doi = 10.1016/j.abb.2005.04.011 }}</ref>
* I-Type: Inducible
** This isoform's name is a result of its increased expression in response to hypoxic stress; its formation is [[Inducible enzyme|induced]] by lack of oxygen. This type is highly expressed in rapidly proliferating cells, especially tumor cells.<ref name="pmid10077634">{{cite journal | vauthors = Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y, Han JH, Metz C, Bucala R | title = An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 3047–52 | date = March 1999 | pmid = 10077634 | pmc = 15892 | doi = }}</ref>
* U-Type: Ubiquitous;<ref name="Manzano_1998">{{cite journal | vauthors = Manzano A, Rosa JL, Ventura F, Pérez JX, Nadal M, Estivill X, Ambrosio S, Gil J, Bartrons R | title = Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase gene (PFKFB3) | journal = Cytogenetics and Cell Genetics | volume = 83 | issue = 3-4 | pages = 214–7 | date = 1998 | pmid = 10072580 | doi = 10.1159/000015181 }}</ref> also known as placental<ref name="Sakai_1996">{{cite journal | vauthors = Sakai A, Kato M, Fukasawa M, Ishiguro M, Furuya E, Sakakibara R | title = Cloning of cDNA encoding for a novel isozyme of fructose 6-phosphate, 2-kinase/fructose 2,6-bisphosphatase from human placenta | journal = Journal of Biochemistry | volume = 119 | issue = 3 | pages = 506–11 | date = March 1996 | pmid = 8830046 | doi = | url = }}</ref> or brain<ref name="Ventura_1995">{{cite journal | vauthors = Ventura F, Ambrosio S, Bartrons R, el-Maghrabi MR, Lange AJ, Pilkis SJ | title = Cloning and expression of a catalytic core bovine brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase | journal = Biochemical and Biophysical Research Communications | volume = 209 | issue = 3 | pages = 1140–8 | date = April 1995 | pmid = 7733968 | doi = }}</ref><ref name="Bando_2005">{{cite journal | vauthors = Bando H, Atsumi T, Nishio T, Niwa H, Mishima S, Shimizu C, Yoshioka N, Bucala R, Koike T | title = Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer | journal = Clinical Cancer Research | volume = 11 | issue = 16 | pages = 5784–92 | date = August 2005 | pmid = 16115917 | doi = 10.1158/1078-0432.CCR-05-0149 }}</ref>
**
** Though discovered separately in the placental, pancreatic-β-islet, or brain tissues, the various isoforms appear identical.<ref name="pmid24280138" /> 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.<ref name="Sakakibara_1997" /><ref name="Riera_2003">{{cite journal | vauthors = Riera L, Obach M, Navarro-Sabaté A, Duran J, Perales JC, Viñals F, Rosa JL, Ventura F, Bartrons R | title = Regulation of ubiquitous 6-phosphofructo-2-kinase by the ubiquitin-proteasome proteolytic pathway during myogenic C2C12 cell differentiation | journal = FEBS Letters | volume = 550 | issue = 1-3 | pages = 23–9 | date = August 2003 | pmid = 12935880 | doi = }}</ref>
** 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.<ref name="Ventura_1992">{{cite journal | vauthors = Ventura F, Rosa JL, Ambrosio S, Pilkis SJ, Bartrons R | title = Bovine brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Evidence for a neural-specific isozyme | journal = The Journal of Biological Chemistry | volume = 267 | issue = 25 | pages = 17939–43 | date = September 1992 | pmid = 1325453 | doi =  }}</ref>
[[File:PFKB3 .png|left|thumb|275x275px|i-PFKB3, Human inducible form]]


== Further reading ==
*
{{refbegin}}
* {{cite journal | vauthors = Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L | title = 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis | journal = Biochem. J. | volume = 381 | issue = Pt 3 | pages = 561–79 |date=August 2004 | pmid = 15170386 | pmc = 1133864 | doi = 10.1042/BJ20040752 | url =  }}
{{refend}}


==External links==
=== PFKB4: Testis (T-Type)  ===
Gene PFKB4, located on chromosome 3, expresses PFK-2 in human testis tissue.<ref name="pmid10095107">{{cite journal | vauthors = Manzano A, Pérez JX, Nadal M, Estivill X, Lange A, Bartrons R | title = Cloning, expression and chromosomal localization of a human testis 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene | journal = Gene | volume = 229 | issue = 1-2 | pages = 83–9 | date = March 1999 | pmid = 10095107 | doi = }}</ref> 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.<ref name="Manzano_1998" /> 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.<ref name="Gómez_2005">{{cite journal | vauthors = Gómez M, Manzano A, Navarro-Sabaté A, Duran J, Obach M, Perales JC, Bartrons R | title = Specific expression of pfkfb4 gene in spermatogonia germ cells and analysis of its 5'-flanking region | journal = FEBS Letters | volume = 579 | issue = 2 | pages = 357–62 | date = January 2005 | pmid = 15642344 | doi = 10.1016/j.febslet.2004.11.096 }}</ref> This isoform has been particularly implicated as being modified and hyper-expressed for prostate cancer cell survival.<ref name="pmid22576210">{{cite journal | vauthors = Ros S, Santos CR, Moco S, Baenke F, Kelly G, Howell M, Zamboni N, Schulze A | title = Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival | journal = Cancer Discovery | volume = 2 | issue = 4 | pages = 328–43 | date = April 2012 | pmid = 22576210 | doi = 10.1158/2159-8290.CD-11-0234 }}</ref>
[[File:PFKB4 Testis isozyme.png|center|thumb|300x300px|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.<ref name="Hasemann_1996" /><ref name="Novellasdemunt_2013" /> 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.<ref name=":3">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.</ref> The control of PFK-2/FBP-ase2 activity was found to be linked to heart functioning, particularly for [[ischemia]], and the control against [[hypoxia (medical)|hypoxia]].<ref name="pmid18456722">{{cite journal | vauthors = Wang Q, Donthi RV, Wang J, Lange AJ, Watson LJ, Jones SP, Epstein PN | title = Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 294 | issue = 6 | pages = H2889-97 | date = June 2008 | pmid = 18456722 | doi = 10.1152/ajpheart.91501.2007 | pmc = 4239994 }}</ref> Researchers hypothesize that this responsive characteristic of the PFK-2 genes may be a strong, evolutionary physiological adaptation.<ref name=":3" /> 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 (oncology)|Warburg effect]].<ref name="Novellasdemunt_2013" /><ref name="Minchenko_2005">{{cite journal | vauthors = Minchenko OH, Opentanova IL, Ogura T, Minchenko DO, Komisarenko SV, Caro J, Esumi H | title = Expression and hypoxia-responsiveness of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 in mammary gland malignant cell lines | journal = Acta Biochimica Polonica | volume = 52 | issue = 4 | pages = 881–8 | date = 2005 | pmid = 16025159 | doi = }}</ref>
 
Lastly, the ''Pfkfb2'' gene encoding PFK2/FBPase2 protein is linked to the predisposition to [[schizophrenia]].<ref name="pmid15108172">{{cite journal | vauthors = Stone WS, Faraone SV, Su J, Tarbox SI, Van Eerdewegh P, Tsuang MT | title = Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 127B | issue = 1 | pages = 5–10 | date = May 2004 | pmid = 15108172 | doi = 10.1002/ajmg.b.20132 }}</ref>
 
== References ==
{{reflist|32em}}
 
== External links ==
* {{MeshName|Fructose+2,6-bisphosphatase}}
* {{MeshName|Fructose+2,6-bisphosphatase}}
* [http://www.genome.jp/dbget-bin/www_bget?ath:AT5G47810 6-phosphofructokinase of Arabidopsis thaliana at genome.jp]
* [http://www.genome.jp/dbget-bin/www_bget?ath:AT5G47810 6-phosphofructokinase of Arabidopsis thaliana at genome.jp]
''This article incorporates text from the [[public domain]] [[Pfam]] and [[InterPro]] [https://www.ebi.ac.uk/interpro/entry/IPR013079 IPR013079]''


{{Glycolysis enzymes}}
{{Glycolysis enzymes}}

Latest revision as of 14:14, 28 September 2018

6-phosphofructo-2-kinase/fructose-bisphosphatase-2
File:Phosphofructokinase 2.jpg
Structure of PFK2. Shown: kinase domain (cyan) and the phosphatase domain (green).
Identifiers
Symbol6PF2K
PfamPF01591
InterProIPR013079
PROSITEPDOC00158
SCOP1bif
SUPERFAMILY1bif
fructose-bisphosphatase-2
Identifiers
SymbolFBPase-2
PfamPF00316
InterProIPR028343
PROSITEPDOC00114

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.

File:PFK-2-FBP-ase 2 Reaction.png
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 <math>\rightleftharpoons</math> 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 <math>\rightleftharpoons</math> 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
File:PDB 1k6m EBI.jpg
Crystal structure of human liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
Identifiers
EC number2.7.1.105
CAS number78689-77-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / 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]
File:Liver Tissue PFK-2 Regulation.png
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
File:5htk.jpg
6-phosphofructo-2-kinase dimer, Human heart tissue
Identifiers
EC number2.7.1.105
CAS number78689-77-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / 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]
File:PFKB3 .png
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]

File:PFKB4 Testis isozyme.png
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. ↑ 1.0 1.1 1.2 1.3 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 2143155. 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 4007419. PMID 24637025.
  3. ↑ 3.0 3.1 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 1133864. PMID 15170386.
  4. ↑ 4.0 4.1 4.2 4.3 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 553140. PMID 6329717.
  8. ↑ 8.0 8.1 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. ↑ 10.0 10.1 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. ↑ 12.0 12.1 12.2 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 298557. PMID 2557623.
  14. ↑ 14.0 14.1 "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. ↑ 16.0 16.1 "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. ↑ 19.0 19.1 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 4178209. PMID 24280138.
  20. ↑ 20.0 20.1 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 297880. 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. ↑ 23.0 23.1 23.2 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 3624444. PMID 23457334.
  24. ↑ 24.0 24.1 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. ↑ 25.0 25.1 25.2 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. ↑ 36.0 36.1 36.2 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 15892. PMID 10077634.
  39. ↑ 39.0 39.1 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. ↑ 47.0 47.1 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 4239994. 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

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