Altered allosteric regulation of muscle 6-phosphofructokinase causes Tarui disease

Tarui disease is a glycogen storage disease (GSD VII) and characterized by exercise intolerance with muscle weakness and cramping, mild myopathy, myoglobinuria and compensated hemolysis. It is caused by mutations in the muscle 6-phosphofructokinase (Pfk). Pfk is an oligomeric, allosteric enzyme which catalyzes one of the rate-limiting steps of the glycolysis: the phosphorylation of fructose 6-phosphate at position 1. Pfk activity is modulated by a number of regulators including adenine nucleotides. Recent crystal structures from eukaryotic Pfk displayed several allosteric adenine nucleotide binding sites. Functional studies revealed a reciprocal linkage between the activating and inhibitory allosteric binding sites. Herein, we showed that Asp543Ala, a naturally occurring disease-causing mutation in the activating binding site, causes an increased efficacy of ATP at the inhibitory allosteric binding site. The reciprocal linkage between the activating and inhibitory binding sites leads to reduced enzyme activity and therefore to the clinical phenotype. Pharmacological blockage of the inhibitory allosteric binding site or highly efficient ligands for the activating allosteric binding site may be of therapeutic relevance for patients with Tarui disease.

► Inactivating mutations in the muscle 6-phosphofructokinase lead to Tarui disease.
► Mutation N543A increases efficacy of ATP at the inhibitory allosteric binding site.
► Increased efficacy of ATP at the allosteric binding site leads to inactivation.
► Altered allosteric regulation of muscle Pfk causes reduced enzyme activity.
► Pfk activity may be rescued by ligands of nucleotide allosteric binding sites.