6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

Target id: 2937

Nomenclature: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

Abbreviated Name: PFKFB3

Family: Sugar phosphatases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 520 10p15.1 PFKFB3 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3
Mouse - 555 2 A1, 8.73 cM Pfkfb3 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3
Rat - 555 17q12.2 Pfkfb3 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3
Gene and Protein Information Comments
Isoform 1 of the human protein is 520 amino acids long, but other transcript variants and isoforms have been detected. In the mouse transcript variant 2 gives rise to the longest protein isoform. To date only one transcript variant has been identified in rat.
Previous and Unofficial Names
iPFK-2 | PFK2
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.1.105
Description Reaction Reference
Kinase activity ATP + D-fructose 6-phosphate <=> ADP + beta-D-fructose 2,6-bisphosphate
EC Number: 3.1.3.46
Description Reaction Reference
Dephosphorylation activity Beta-D-fructose 2,6-bisphosphate + H(2)O <=> D-fructose 6-phosphate + phosphate

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
PFK15 Hs Inhibition 6.7 pIC50 3
pIC50 6.7 (IC50 2.07x10-7 M) [3]
Description: Inhibition of kinase activity in a biochemical assay.
Immunopharmacology Comments
Inhibition of PFKFB3 is being investigated for clinical utility primarily in cancer, but also as a novel intervention for joint inflammation in rheumatoid arthritis (RA) [8].
Physiological Consequences of Altering Gene Expression
Disruption of Pfkb3 results in embryonic lethality, identifying the activity of the iPFK2 enzyme (i.e. activation of anaerobic glycolysis within the hypoxic microenvironment of the enbryo prior to vasculogenesis) as critical for survival of the growing embryo.
Species:  Mouse
Tissue: 
Technique: 
References:  2
General Comments
PFKFB3 is one of four tissue-specific PFKFB isoenzymes identified in humans. Enzymes of this family are bifunctional enzymes that catalyze opposing reactions (synthesis and degradation) of fructose-2,6-bisphosphate (F2,6BP). Structurally each family member has a kinase domain (at the amino terminus, the synthetic function) and a bisphosphatase domain (at the carboxy terminus, the degrading function) [4]. They acts as metabolic signaling enzymes catalyzing the conversion of F2,6BP [6]. The F2,6BP generated by enzyme activity stimulates glycolysis via activation of phosphofructokinase 1 (PFK-1; an important regulator of glycolysis that converts fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP).
The primary protein encoded by PFKFB3 is iPFK2 (an inducible isoform, upregulated by hypoxia-inducible factor 1α [5], and by inflammatory stimuli [1]). PFKFB3 is most widely recognised for its association with the upregulated glycolysis observed in cancer cells which underlies the so-called Warburg effect [1,5,7]. Induction or overexpression of PFKFB3 can trigger a shift to the glycolytic pathway even in the presence of oxygen, an event that strongly supports cancerous growth. It also has effects on angiogenesis, cell cycle and apoptosis, additional processes involved in cancer growth. As a drug target, PFKFB3 inhibitors are in clinical development as anti-cancer therapies (e.g. optimised derivatives of the small molecule inhibitor 3PO (3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one) such as PFKF15 [3].

References

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1. Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y, Han JH, Metz C, Bucala R. (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. Proc. Natl. Acad. Sci. U.S.A.96 (6): 3047-52. [PMID:10077634]

2. Chesney J, Telang S, Yalcin A, Clem A, Wallis N, Bucala R. (2005) Targeted disruption of inducible 6-phosphofructo-2-kinase results in embryonic lethality. Biochem. Biophys. Res. Commun.331 (1): 139-46. [PMID:15845370]

3. Clem BF, O'Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr 2nd DA, Klarer AC, Redman R, Miller DM, Trent JO et al.. (2013) Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol. Cancer Ther.12 (8): 1461-70. [PMID:23674815]

4. 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). Cytogenet. Cell Genet.83 (3-4): 214-7. [PMID:10072580]

5. Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, Caro J. (2002) Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J. Biol. Chem.277 (8): 6183-7. [PMID:11744734]

6. Pilkis SJ, Claus TH, Kurland IJ, Lange AJ. (1995) 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: a metabolic signaling enzyme. Annu. Rev. Biochem.64: 799-835. [PMID:7574501]

7. WARBURG O. (1956) On the origin of cancer cells. Science123 (3191): 309-14. [PMID:13298683]

8. Zou Y, Zeng S, Huang M, Qiu Q, Xiao Y, Shi M, Zhan Z, Liang L, Yang X, Xu H. (2017) Inhibition of 6-phosphofructo-2-kinase suppresses fibroblast-like synoviocytes-mediated synovial inflammation and joint destruction in rheumatoid arthritis. Br. J. Pharmacol.174 (9): 893-908. [PMID:28239846]

How to cite this page

Sugar phosphatases: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3. Last modified on 09/05/2017. Accessed on 19/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2937.