Allosteric Regulation in Pyruvate Kinase Function

Pyruvate kinase occupies a central role in glycolysis, catalysing the conversion of phosphoenolpyruvate to pyruvate with concomitant ATP generation. Its activity is finely tuned by allosteric effectors that bind at sites distinct from the catalytic centre, inducing conformational transitions between inactive (T) and active (R) states. In eukaryotic and prokaryotic isoforms alike, fructose 1,6-bisphosphate, glucose-6-phosphate and adenine nucleotides serve as principal modulators, altering quaternary interactions within the tetramer and reshaping dynamic networks of salt bridges and hydrogen bonds. This allosteric control enables rapid adaptation of glycolytic flux to fluctuating energy demands, nutrient availability and stress signals. Dysregulation of pyruvate kinase has been linked to metabolic disorders, cancer cell proliferation and microbial pathogenicity, making the enzyme a widely pursued target for therapeutic intervention. Recent advances in structural biology and small-molecule screening have uncovered cryptic binding pockets and distinct activation mechanisms across species, offering prospects for isoform-selective modulation and improved understanding of metabolic homeostasis.

Research from Nature Portfolio

Recent studies have characterised a molecular “OR logic gate” in Mycobacterium tuberculosis pyruvate kinase whereby AMP and glucose-6-phosphate function as synergistic activators. Structural analyses revealed that glucose-6-phosphate binds at a previously unrecognised site adjacent to the canonical AMP pocket, triggering cooperative stabilisation of the active tetrameric form. Kinetic and network modelling demonstrated that dual effector binding enhances conformational coupling between subunits, while metabolomic profiling of Mycobacterium bovis BCG under nutrient deprivation highlighted dynamic shifts in intracellular effector levels. These findings illuminate how multi-ligand allostery endows bacterial pyruvate kinase with robust control over energy and carbon metabolism, revealing potential metabolic vulnerabilities during infection.

Allosteric Regulation in Pyruvate Kinase Function publication trend

The graph below shows the total number of articles in allosteric regulation in pyruvate kinase function across all publications each year (not limited to Nature Index journals).

Technical terms

Allosteric regulation: Modulation of enzyme activity through binding of molecules at sites other than the active site, inducing conformational changes.

Effector: A metabolite or small molecule that binds allosteric sites to enhance (activator) or reduce (inhibitor) catalytic activity.

Tetramer: A quaternary structure composed of four subunits, often required for cooperative interactions in allosteric enzymes.

Conformational dynamics: The ensemble of structural states and transitions that an enzyme undergoes during regulation and catalysis.

Structure–activity relationship: The correlation between chemical modifications of a compound and its effect on biological activity, used to guide the design of modulators.

References

1. Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators. European Journal of Medicinal Chemistry (2023).
2. Structural Basis of Nucleotide Selectivity in Pyruvate Kinase. Journal of Molecular Biology (2024).
3. Functional and structural characterization of Streptococcus pneumoniae pyruvate kinase involved in fosfomycin resistance. Journal of Biological Chemistry (2023).
4. Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis. Nature Communications (2017).