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Literature summary for 2.7.1.105 extracted from
- Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism (2013), Cancer Metab., 1, 8.
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| Insulin | stimulates glycolysis in the heart by increasing glucose transport and activating H-PFK2 by phosphorylating Ser466 and Ser483 through protein kinase B within the C-terminal regulatory domain. Phosphorylation of Ser466 or Thr475 by protein kinase C does not change the enzyme activity. Phosphorylation at Ser84 possibly counteracts the effects of phosphorylation at the activating C-terminal sites | Homo sapiens |
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | PFK-2/FBPase-2 enzymes is attractive targets for cancer treatment | Homo sapiens |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene PFKFB1, located on chromosome Xp11.21, the PFKFB1 gene contains 17 exons and encodes 3 different mRNAs L, M and F | Homo sapiens |
| gene PFKFB2, located on chromosome 1q31, encodes the heart isozyme, the PFKFB2 gene encodes four different mRNAs that are derived from different promoters and that vary only in non-coding sequences at the 5'-end | Homo sapiens |
| gene PFKFB3, located on chromosome 10p14-p15, gene PFKFB3 contains at least 19 exons and generates at least 6 different transcripts by alternative splicing. The resulting polypeptides differ in the length of their C-terminal variable regions that are encoded by the last seven exons. Alternative splicing of exon 15 generates the two main isoforms that differ by a short C-terminal sequence: the ubiquitous PFK2 (U-PFK2, 15 exons) and the inducible PFK2 (I-PFK2, 16 exons) isoforms | Homo sapiens |
| gene PFKFB4, located on chromosome 3p21-p22, the gene contains at least 14 exons, and several splice variants of the PFKFB4 mRNA | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 2-(2-bromoacetamido)ethyl phosphate | an irreversible inhibitor of PFK-2 in several cancer cell lines | Homo sapiens |  |
| 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one | - |
Homo sapiens | |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | required | Homo sapiens | |
Molecular Weight [Da]
| Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
|---|---|---|---|
| 54000 | - |
- |
Homo sapiens |
| 58000 | - |
- |
Homo sapiens |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + beta-D-fructose 6-phosphate | Homo sapiens | - |
ADP + beta-D-fructose 2,6-bisphosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | O60825 | isozyme PFKFB2 | - |
| Homo sapiens | P16118 | isozyme PFKFB1 | - |
| Homo sapiens | Q16875 | isozyme PFKFB3, variant I-PFK2 is inducible | - |
| Homo sapiens | Q16877 | isozyme PFKFB4 | - |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| phosphoprotein | in response to glucagon, cyclic AMP-dependent protein kinase phosphorylates Ser32 in the liver isoform variant of PFKFB1, leading to inactivation of its PFK-2 activity while activating its FBPase-2 function. Two serine residues, Ser466 and Ser483, within the C-terminal regulatory domain of PFKFB2 can be phosphorylated by protein kinase B (Akt/PKB) in response to insulin | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| brain | isozyme U-PFK2 | Homo sapiens | - |
| breast cancer cell | - |
Homo sapiens | - |
| colon cancer cell | - |
Homo sapiens | - |
| fetus | isozyme variant F-PFK2 | Homo sapiens | - |
| gastric cancer cell | - |
Homo sapiens | - |
| heart | long isozyme variants H1-PFK2, H2-PFK2, and H4-PFK2, and short isozyme variant H3-PFK2 | Homo sapiens | - |
| liver | isozyme variant L-PFK2 | Homo sapiens | - |
| lung cancer cell | - |
Homo sapiens | - |
| additional information | isozyme PFKFB3 variants are ubiquitously expressed, the variant I-PFK2 is inducible | Homo sapiens | - |
| additional information | PFKFB4 expression is induced in breast, colon, lung, gastric and pancreatic cancer cell lines | Homo sapiens | - |
| muscle | isozyme variant M-PFK2 | Homo sapiens | - |
| pancreatic cancer cell | - |
Homo sapiens | - |
| placenta | isozyme U-PFK2 | Homo sapiens | - |
| prostate cancer cell | - |
Homo sapiens | - |
| testis | isozyme variant T-PFK2 | Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + beta-D-fructose 6-phosphate | - |
Homo sapiens | ADP + beta-D-fructose 2,6-bisphosphate | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| ? | x * 58000, long isozyme variants H1-PFK2, H2-PFK2, and H4-PFK2, x * 54000, short isozyme variant H3-PFK2 | Homo sapiens |
| More | domain organization of isozyme PFKFB1 tissue variants, overview | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase | - |
Homo sapiens |
| PFKFB1 | - |
Homo sapiens |
| PFKFB2 | - |
Homo sapiens |
| PFKFB3 | - |
Homo sapiens |
| PFKFB4 | - |
Homo sapiens |
| T-PFK2 | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Homo sapiens | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | isozyme PFKFB3 variant I-PFK2 is inducible | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | silencing of PFKFB4 results in increased levels of Fru-2,6-P2 in prostate cancer cells, knockdown of PFKFB4 blocks prostate cancer cell growth and remarkably induced regression of prostate tumor xenografts | Homo sapiens |
| metabolism | fructose 2,6-bisphosphate is an important metabolite for the dynamic regulation of glycolytic flux by allosterically activating the rate-limiting enzyme of glycolysis phosphofructokinase-1, fructose 2,6-bisphosphate is a powerful allosteric activator of phosphofructokinase 1, PFK-1 | Homo sapiens |
| physiological function | possible role of different isozyme PFKFB4 splice variants in cell-specific and/or tissue-specific regulation of glycolysis, role of PFKFB proteins in the control of cancer metabolism. PFKFB4 may be important for cancer cell survival, PFKFB4 plays an essential role in the survival of glioma stem-like cells and of prostate cancer cells. PFKFB4 is known to be a component of the HIF-mediated response to hypoxia, hypoxic induction of PFKFB4 is mediated by a hypoxia response element (HRE) in the promoter region of the PFKFB4 gene | Homo sapiens |
| physiological function | role of PFKFB proteins in the control of cancer metabolism | Homo sapiens |
| physiological function | role of PFKFB proteins in the control of cancer metabolism. Liver, muscle and fetal isoform variants of PFKFB1 (L-PFK2, M-PFK2 and F-PFK2 respectively) are transcribed from the same gene, but only L-PFK2 contains a serine residue in position 32 of its C-terminal regulatory domain. This is consistent with its specific physiological role as liver cells need to modulate Fru-2,6-P2 levels to facilitate the production of glucose to fulfill the metabolic demand of other tissues. Response to glucagon, cyclic AMP-dependent protein kinase (PKA) phosphorylates Ser32 in the liver isoform of PFKFB1, leads to inactivation of its PFK-2 activity while activating its FBPase-2 function. This decreases glycolytic flux while increasing gluconeogenesis in liver cells While phosphorylation of L-PFK2 results in a decrease in its kinase activity, phosphorylation of H-PFK2 results in an increase in this activity | Homo sapiens |
| physiological function | role of PFKFB proteins in the control of cancer metabolism. PFKFB3 is known to be a component of the HIF-mediated response to hypoxia. PFKFB3 is a hypoxia-inducible gene that is stimulated through the interaction of HIF-1alpha with a consensus HRE within its promoter region | Homo sapiens |
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