| Property | Value |
|---|---|
| **Protein Name** | 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase 3 (PFKFB3) |
| **Gene** | [PFKFB3](/genes/pfbkfb3) |
| **UniProt** | [Q9H8X0](https://www.uniprot.org/uniprot/Q9H8X0) |
| **PDB** | 7R7K, 6OXN |
| **Molecular Weight** | ~58 kDa (monomer) |
| **Subcellular Localization** | Cytoplasm, Nucleus |
| **Protein Family** | PFKFB family (bifunctional kinase/phosphatase) |
PFKFB3 Protein is a protein involved in various cellular processes. ## Structure
PFKFB3 is a ~58 kDa bifunctional enzyme containing two functional domains: an N-terminal kinase domain (~300 aa) that synthesizes fructose-2,6-bisphosphate (F2,6BP) and a C-terminal phosphatase domain (~350 aa) that degrades F2,6BP. The enzyme exists as a homodimer. Unlike other PFKFB isoforms, PFKFB3 contains a nuclear localization signal (NLS) and can translocate to the nucleus, where it may regulate glycolytic gene expression through F2,6BP-dependent mechanisms.
PFKFB3 produces fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of phosphofructokinase-1 (PFK-1), the rate-limiting enzyme of glycolysis. In the brain:
- Neuronal glycolysis: PFKFB3 activity directly controls glycolytic flux in neurons
- Astrocyte metabolism: Regulates glycolysis in astrocytes, important for neurotransmitter recycling
- Gene regulation: Nuclear PFKFB3 may influence glycolytic enzyme expression
- Cell cycle: PFKFB3 is upregulated in proliferating cells including neural progenitors
PFKFB3 is highly expressed in brain tissue, particularly in regions with active neurogenesis and high metabolic demand.
- Increased PFKFB3 in AD: Studies show elevated PFKFB3 expression in AD brain, possibly as a compensatory response to energy failure 1
- F2,6BP dysregulation: Altered F2,6BP levels affect glycolysis in AD neurons
- Therapeutic potential: Inhibiting PFKFB3 may reduce abnormal glycolysis in AD
- PFKFB3 is upregulated in PD substantia nigra
- May contribute to altered metabolism in dopaminergic neurons
- Targeting PFKFB3 could modulate glycolytic flux in PD 2
¶ Stroke and Brain Injury
- PFKFB3 plays a protective role in ischemic conditions
- Enhancing PFKFB3 activity improves outcomes in stroke models 3
PFKFB3 is a promising therapeutic target:
- Inhibitors: PFKFB3 inhibitors (e.g., PFK158) are in clinical trials for cancer and may have applications in neurodegeneration
- Activators: F2,6BP analogs or PFKFB3 activators could enhance brain glycolysis
- Isoform-selective compounds: Selective targeting of brain PFKFB3 may avoid peripheral effects
- PFKFB3 in Alzheimer's disease brain (2017)
- PFKFB3 in Parkinson's disease (2020)
- PFKFB3 in ischemic stroke (2015)
- Fructose-2,6-bisphosphate in brain metabolism (2019)