Phosphofructokinase 2

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6-phosphofructo-2-kinase
5htk.jpg
6-phosphofructo-2-kinase dimer, Human heart
Identifiers
EC no. 2.7.1.105
CAS no. 78689-77-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
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NCBI proteins
6PF2K
PDB 1k6m EBI.jpg
crystal structure of human liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
Identifiers
Symbol6PF2K
Pfam PF01591
Pfam clan CL0023
InterPro IPR013079
PROSITE PDOC00158
SCOP2 1bif / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
6-phosphofructo-2-kinase/fructose-bisphosphatase-2
Phosphofructokinase 2.jpg
Structure of PFK2. Shown: kinase domain (cyan) and the phosphatase domain (green).
Identifiers
Symbol6PF2K
Pfam PF01591
InterPro IPR013079
PROSITE PDOC00158
SCOP2 1bif / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 2axn ​ A:24-246; 1k6m ​ B:40-251; 2bif ​ A:30-249; 3bif ​ A:30-249; 1bif ​ :37-249
fructose-bisphosphatase-2
Identifiers
SymbolFBPase-2
Pfam PF00316
InterPro IPR028343
PROSITE PDOC00114
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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] 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. [3] 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. [4]

Contents

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. [5] One terminus serves as a kinase domain (for PFK-2) while the other terminus acts as a phosphatase domain (FBPase-2). [6]

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. [7]

Structure

The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N-terminal. [8] It consists of a central six-stranded β sheet, with five parallel strands and an antiparallel edge strand, surrounded by seven α helices. [6] The domain contains nucleotide-binding fold (nbf) at the C-terminal end of the first β-strand. [9] The PFK-2 domain appears to be closely related to the superfamily of mononucleotide binding proteins including adenylate cyclase. [10]

On the other hand, the phosphatase domain is located on the C-terminal. [11] It resembles the family of proteins that include phosphoglycerate mutases and acid phosphatases. [10] [12] 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. [6] Finally, the N-terminal region modulates PFK-2 and FBPase2 activities, and stabilizes the dimer form of the enzyme. [12] [13]

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. [14] 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. [15]

Function

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

PFK-2 and FBPase-2 Reaction 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 ADP + beta-D-fructose 2,6-bisphosphate [16]

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. [17]

At the other terminal, the fructose-2,6-bisphosphate 2-phosphatase (EC 3.1.3.46) domain dephosphorylates Fru-2,6-P2 with the addition of water. This opposing chemical reaction is:
beta-D-fructose 2,6-bisphosphate + H2O D-fructose 6-phosphate + phosphate [18]

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. [16] On the other hand, the phosphatase reaction is characteristic of the family of hydrolases, specifically those acting on phosphoric monoester bonds. [18]

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. [19]

Furthermore, the allosteric regulation of PFK2 is very similar to the regulation of PFK1. [20] 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. [21]

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. [5]

Multiple mammalian isoforms of the protein have been reported to date, difference rising by either the transcription of different enzymes or alternative splicing. [22] [23] [24] 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. [14] 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] [14] Each variant differs in their primary tissue of expression, response to protein kinase regulation, and ratio of kinase/phosphatase domain activity. [25] While multiple types of isozymes may consist in a tissue, isozymes are identified by their primary tissue expression and tissue of discovery below. [26]

PFKB1: Liver, muscle, and fetal

6-phosphofructo-2-kinase: PFKB1
PDB 1k6m EBI.jpg
Crystal structure of human liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
Identifiers
EC no. 2.7.1.105
CAS no. 78689-77-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins

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. [22] Variable mRNA splicing of PFKB1 yields three different promoters (L, M and F) and therefore, three tissue-specific variants that differ in regulation: [27]

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. 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.
6-phosphofructo-2-kinase: PFKB2
5htk.jpg
6-phosphofructo-2-kinase dimer, Human heart tissue
Identifiers
EC no. 2.7.1.105
CAS no. 78689-77-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins

PFKB2: Cardiac (H-Type)

The PFKB2 gene is located on chromosome 1. [32] 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. [3] Alternatively, Protein Kinase B may also phosphorylate these regulatory sites, which are part of the FBPase-2 domain. [33] When this serine residue is phosphorylated, FBPase-2 function is inactivated and greater PFK-2 activity is stabilized. [27]

PFKB3: Brain, placental, and inducible

PFKB3 is located on chromosome 10 and transcribes two major isoforms, inducible type and ubiquitous type. [34] These forms differ in alternative splicing of Exon 15 in their C-terminus. [35] 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. [36] 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). [37] Therefore, PFKB3 in particular consistently produces large amounts of F-2,6-P2 and sustains high rates of glycolysis. [37] [38]

i-PFKB3, Human inducible form PFKB3 .png
i-PFKB3, Human inducible form

PFKB4: Testis (T-Type)

Gene PFKB4, located on chromosome 3, expresses PFK-2 in human testis tissue. [46] 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. [40] 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. [26] This isoform has been particularly implicated as being modified and hyper-expressed for prostate cancer cell survival. [47]

6-phosphofructo-2-kinase structure, testis tissue 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. [6] [25] 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. [48] 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. [25] [50]

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

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Fructose 1,6-bisphosphatase</span> Class of enzymes

The enzyme fructose bisphosphatase (EC 3.1.3.11; systematic name D-fructose-1,6-bisphosphate 1-phosphohydrolase) catalyses the conversion of fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle, which are both anabolic pathways:

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironments in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumor vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Phosphofructokinase 1</span> Class of enzymes

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important "committed" step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. Glycolysis is the foundation for respiration, both anaerobic and aerobic. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory steps of glycolysis. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell's energy requirements. For example, a high ratio of ATP to ADP will inhibit PFK and glycolysis. The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2,6-bisphosphate. The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.

<span class="mw-page-title-main">PFP (enzyme)</span>

Diphosphate—fructose-6-phosphate 1-phosphotransferase also known as PFP is an enzyme of carbohydrate metabolism in plants and some bacteria. The enzyme catalyses the reversible interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate using inorganic pyrophosphate as the phosphoryl donor:

A futile cycle, also known as a substrate cycle, occurs when two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat. The reason this cycle was called "futile" cycle was because it appeared that this cycle operated with no net utility for the organism. As such, it was thought of being a quirk of the metabolism and thus named a futile cycle. After further investigation it was seen that futile cycles are very important for regulating the concentrations of metabolites. For example, if glycolysis and gluconeogenesis were to be active at the same time, glucose would be converted to pyruvate by glycolysis and then converted back to glucose by gluconeogenesis, with an overall consumption of ATP. Futile cycles may have a role in metabolic regulation, where a futile cycle would be a system oscillating between two states and very sensitive to small changes in the activity of any of the enzymes involved. The cycle does generate heat, and may be used to maintain thermal homeostasis, for example in the brown adipose tissue of young mammals, or to generate heat rapidly, for example in insect flight muscles and in hibernating animals during periodical arousal from torpor. It has been reported that the glucose metabolism substrate cycle is not a futile cycle but a regulatory process. For example, when energy is suddenly needed, ATP is replaced by AMP, a much more reactive adenine.

<span class="mw-page-title-main">Fructose 2,6-bisphosphate</span> Chemical compound

Fructose 2,6-bisphosphate, abbreviated Fru-2,6-P2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. Fru-2,6-P2 itself is synthesized and broken down in either direction by the integrated bifunctional enzyme phosphofructokinase 2 (PFK-2/FBPase-2), which also contains a phosphatase domain and is also known as fructose-2,6-bisphosphatase. Whether the kinase and phosphatase domains of PFK-2/FBPase-2 are active or inactive depends on the phosphorylation state of the enzyme.

<span class="mw-page-title-main">Phosphofructokinase</span> Enzyme in glycolysis

Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.

<span class="mw-page-title-main">Fructose-bisphosphate aldolase</span>

Fructose-bisphosphate aldolase, often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P). Aldolase can also produce DHAP from other (3S,4R)-ketose 1-phosphates such as fructose 1-phosphate and sedoheptulose 1,7-bisphosphate. Gluconeogenesis and the Calvin cycle, which are anabolic pathways, use the reverse reaction. Glycolysis, a catabolic pathway, uses the forward reaction. Aldolase is divided into two classes by mechanism.

Glucose-1,6-bisphosphate synthase is a type of enzyme called a phosphotransferase and is involved in mammalian starch and sucrose metabolism. It catalyzes the transfer of a phosphate group from 1,3-bisphosphoglycerate to glucose-1-phosphate, yielding 3-phosphoglycerate and glucose-1,6-bisphosphate.

<span class="mw-page-title-main">PFKM</span> Mammalian protein found in Homo sapiens

6-phosphofructokinase, muscle type is an enzyme that in humans is encoded by the PFKM gene on chromosome 12. Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

<span class="mw-page-title-main">PFKFB3</span> Protein-coding gene in the species Homo sapiens

PFKFB3 is a gene that encodes the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme in humans. It is one of 4 tissue-specific PFKFB isoenzymes identified currently (PFKFB1-4).

<span class="mw-page-title-main">PFKL</span> Mammalian protein found in Homo sapiens

6-phosphofructokinase, liver type (PFKL) is an enzyme that in humans is encoded by the PFKL gene on chromosome 21. This gene encodes the liver (L) isoform of phosphofructokinase-1, an enzyme that catalyzes the conversion of D-fructose 6-phosphate to D-fructose 1,6-bisphosphate, which is a key step in glucose metabolism (glycolysis). This enzyme is a tetramer that may be composed of different subunits encoded by distinct genes in different tissues. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

<span class="mw-page-title-main">PFKP</span> Mammalian protein found in Homo sapiens

Phosphofructokinase, platelet, also known as PFKP is an enzyme which in humans is encoded by the PFKP gene.

<span class="mw-page-title-main">PFKFB2</span> Protein-coding gene in the species Homo sapiens

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 is an enzyme that in humans is encoded by the PFKFB2 gene.

<span class="mw-page-title-main">PFKFB1</span> Protein-coding gene in the species Homo sapiens

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 is an enzyme that in humans is encoded by the PFKFB1 gene.

Bisphosphate may refer to:

<span class="mw-page-title-main">PFKFB4</span> Protein-coding gene in the species Homo sapiens

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 also known as PFKFB4 is an enzyme which in humans is encoded by the PFKFB4 gene.

<span class="mw-page-title-main">TP53-inducible glycolysis and apoptosis regulator</span> Protein-coding gene in the species Homo sapiens

The TP53-inducible glycolysis and apoptosis regulator (TIGAR) also known as fructose-2,6-bisphosphatase TIGAR is an enzyme that in humans is encoded by the C12orf5 gene.

References

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  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. 1 2 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. doi: 10.1046/j.1432-1327.1998.2540103.x . PMID   9652401.
  4. ↑ Wang X, Deng Z, Kemp RG (September 1998). "An essential methionine residue involved in substrate binding by phosphofructokinases". Biochem. Biophys. Res. Commun. 250 (2): 466–8. doi:10.1006/bbrc.1998.9311. PMID   9753654.
  5. 1 2 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.
  6. 1 2 3 4 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. doi:10.1002/j.1460-2075.1982.tb01276.x. PMC   553140 . PMID   6329717.
  10. 1 2 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.
  11. ↑ 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. doi: 10.1016/S0021-9258(19)36651-7 . PMID   1328239.
  12. 1 2 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.
  13. ↑ 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. doi: 10.1016/S0021-9258(18)82344-4 . PMID   8393455.
  14. 1 2 3 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. doi:10.1097/00075197-200109000-00012. PMID   11568503. S2CID   6638455.
  15. ↑ 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. Bibcode:1989PNAS...86.9642B. doi: 10.1073/pnas.86.24.9642 . PMC   298557 . PMID   2557623.
  16. 1 2 "ENZYME entry 2.7.1.105". enzyme.expasy.org. Retrieved 2018-03-24.
  17. ↑ "6-phosphofructo-2-kinase (IPR013079)". InterPro. EMBL-EBI. Retrieved 2018-03-25.
  18. 1 2 "ENZYME entry 3.1.3.46". enzyme.expasy.org. Retrieved 2018-03-25.
  19. ↑ 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. doi:10.1016/S0968-0004(00)01699-6. PMID   11165514.
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