PFKM

PFKM is the gene that encodes the muscle-type isoform of phosphofructokinase-1 (PFK-1), a key enzyme in glycolysis. PFK-1 catalyzes the ATP-dependent phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate, a rate-limiting step that helps regulate glycolytic flux according to cellular energy demands.

The enzyme is a tetramer and can include subunits encoded by three genes: PFKM (muscle type), PFKL (liver type), and PFKP (platelet type). The PFKM product predominantly contributes to the muscle isozyme, which is abundant in skeletal and cardiac muscle and participates in rapid glycolytic throughput during contraction. The assembly into homotetramers or heterotetramers allows tissue-specific regulation of glycolysis.

PFK-1 activity is under strong allosteric control. It is activated by AMP and fructose 2,6-bisphosphate, signaling a need for increased glycolytic throughput, and inhibited by ATP and citrate when energy is abundant. Fructose 2,6-bisphosphate levels are regulated by specialized PFK-2/FBPase enzymes, linking hormonal and metabolic cues to glycolysis.

Clinical significance: Mutations in PFKM cause Tarui disease, or glycogen storage disease type VII, an autosomal recessive metabolic myopathy. Patients typically present with exercise-induced muscle pain, cramps, weakness, and myoglobinuria following exertion. Diagnosis involves clinical assessment, enzymatic testing showing reduced PFK-1 activity in muscle, and genetic testing confirming PFKM variants.

Research and regulation: PFKM expression is controlled by muscle differentiation programs and energy-sensing pathways, including AMPK signaling. The M subunit participates in forming the functional PFK-1 tetramer, enabling muscle-specific regulation of the glycolytic pathway.