| Property | Value |
|---|---|
| **Protein Name** | Phosphofructokinase, Liver (PFKL) |
| **Gene** | [PFKL](/genes/pfkl) |
| **UniProt** | [P31182](https://www.uniprot.org/uniprot/P31182) |
| **PDB** | 4XON, 5AUY |
| **Molecular Weight** | ~780 kDa (tetramer) |
| **Subcellular Localization** | Cytoplasm |
| **Protein Family** | Phosphofructokinase family |
PFKL Protein is a protein involved in various cellular processes. ## Structure
PFKL is a 780 kDa tetrameric enzyme composed of four identical ~55 kDa subunits. The enzyme contains two binding sites for ATP (one catalytic, one allosteric) and binding sites for fructose-6-phosphate and fructose-1,6-bisphosphate. The active site is located at the interface between subunits, while the allosteric regulatory site is distinct. PFKL is allosterically regulated by multiple metabolites including ADP/AMP (activators), ATP (inhibitor at high concentrations), and citrate (inhibitor).
In the brain, PFKL plays a critical role in neuronal energy metabolism by catalyzing the rate-limiting step of glycolysis: the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Neurons rely heavily on glucose metabolism for ATP production, and PFKL activity directly influences glycolytic flux and energy supply. The enzyme is expressed in neurons and astrocytes, with particular importance in regions with high metabolic demand such as the hippocampus and cerebral cortex.
PFKL regulation in the brain involves:
- Energy sensing: ADP and AMP activate PFKL to increase glycolysis during periods of high energy demand
- Neurotransmitter metabolism: Glycolytic flux supports glutamate reuptake and neurotransmitter recycling
- Ion homeostasis: ATP from glycolysis fuels Na+/K+ ATPase and calcium pumps
PFKL dysfunction has been implicated in AD through several mechanisms:
- Metabolic Hypoxia: Reduced PFKL activity in AD brain may contribute to neuronal energy failure and contribute to amyloid toxicity 1
- Glycolytic Impairment: Post-mortem studies show decreased PFKL activity in AD hippocampus 2
- Glucose Hypometabolism: FDG-PET studies in AD show reduced cerebral glucose metabolism that may involve PFKL dysregulation 3
- Reduced PFKL expression has been observed in PD substantia nigra
- PFKL may be affected by mitochondrial dysfunction in PD 4
- Glycolytic impairment contributes to dopaminergic neuron vulnerability
PFKL is being investigated as a therapeutic target:
- Allosteric Activators: Small molecules that activate PFKL could enhance brain glycolysis
- Fructose-2,6-bisphosphate analogs: Metabolic intermediates that activate PFKL
- Gene therapy: AAV-mediated PFKL delivery to enhance neuronal metabolism
- Altered glycolysis in Alzheimer's disease brain (2020)
- Phosphofructokinase activity in AD brain (2015)
- Brain glucose metabolism in MCI and AD (2014)
- Mitochondrial dysfunction and glycolysis in PD (2015)