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

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2937

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

Abbreviated Name: PFKFB3

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
6-phosphofructo-2-kinase/fructose-2 \| iPFK-2 \| PFK2

Previous and Unofficial Names

6-phosphofructo-2-kinase/fructose-2 | iPFK-2 | PFK2

Database Links
Alphafold	Q16875 (Hs), O35552 (Rn)
BRENDA	2.7.1.105, 3.1.3.46
CATH/Gene3D	3.40.50.1240
ChEMBL Target	CHEMBL2331053 (Hs)
Ensembl Gene	ENSG00000170525 (Hs), ENSMUSG00000026773 (Mm), ENSRNOG00000018911 (Rn)
Entrez Gene	5209 (Hs), 170768 (Mm), 117276 (Rn)
Human Protein Atlas	ENSG00000170525 (Hs)
KEGG Enzyme	2.7.1.105, 3.1.3.46
KEGG Gene	hsa:5209 (Hs), mmu:170768 (Mm), rno:117276 (Rn)
OMIM	605319 (Hs)
Pharos	Q16875 (Hs)
RefSeq Nucleotide	NM_004566 (Hs), NM_001177753 (Mm), NM_057135 (Rn)
RefSeq Protein	NP_004557 (Hs), NP_001171224 (Mm), NP_476476 (Rn)
UniProtKB	Q16875 (Hs), O35552 (Rn)
Wikipedia	PFKFB3 (Hs)

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

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Ligand		Sp.	Action	Value	Parameter	Reference
PFKFB3 kinase Inhibitor 69		Hs	Inhibition	7.8	pIC₅₀	1
⤷	pIC₅₀ 7.8 (IC₅₀ 1.4x10^-8 M) [1] Description: In a biochemical assay using purified recombinant human His-tagged PFKFB3, and the production of ADP as readout (ADP-Glo™ Kinase Assay kit from Promega)
PFK15		Hs	Inhibition	6.7	pIC₅₀	4
⤷	pIC₅₀ 6.7 (IC₅₀ 2.07x10^-7 M) [4] 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) [9].

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) [9].

Physiological Consequences of Altering Gene Expression

Disruption of Pfkb3 results in embryonic lethality, identifying the activity of the inducible PFK2 enzyme (i.e. activation of anaerobic glycolysis within the hypoxic microenvironment of the embryo prior to vasculogenesis) as critical for survival of the growing embryo.

Species:	Mouse
Tissue:
Technique:
References:	3

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) [5]. They acts as metabolic signaling enzymes catalyzing the conversion of F2,6BP [7]. 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 [6], and by inflammatory stimuli [2]). PFKFB3 is most widely recognised for its association with the upregulated glycolysis observed in cancer cells which underlies the so-called Warburg effect [2,6,8]. 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 PFK15 [4].

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) [5]. They acts as metabolic signaling enzymes catalyzing the conversion of F2,6BP [7]. 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 [6], and by inflammatory stimuli [2]). PFKFB3 is most widely recognised for its association with the upregulated glycolysis observed in cancer cells which underlies the so-called Warburg effect [2,6,8]. 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 PFK15 [4].

References

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1. Boutard N, Białas A, Sabiniarz A, Guzik P, Banaszak K, Biela A, Bień M, Buda A, Bugaj B, Cieluch E et al.. (2019) Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors. ChemMedChem, 14 (1): 169-181. [PMID:30378281]

2. 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 USA, 96 (6): 3047-52. [PMID:10077634]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. WARBURG O. (1956) On the origin of cancer cells. Science, 123 (3191): 309-14. [PMID:13298683]

9. 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 02/11/2018. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2937.

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

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