Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
Biochem Biophys Res Commun. 2012 Oct 12;427(1):133-7. doi: 10.1016/j.bbrc.2012.09.024. Epub 2012 Sep 17.
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 Asp(543)Ala, 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.
陶赖因病是一种糖原贮积病（GSD VII），其特征为运动不耐受伴肌肉无力和痉挛、轻度肌病、肌红蛋白尿和代偿性溶血。它是由肌肉 6-磷酸果糖激酶（Pfk）的突变引起的。Pfk 是一种寡聚体、变构酶，催化糖酵解的限速步骤之一：在位置 1 上将果糖 6-磷酸磷酸化。Pfk 活性受多种调节剂的调节，包括腺嘌呤核苷酸。来自真核 Pfk 的最近晶体结构显示了几个变构腺嘌呤核苷酸结合位点。功能研究揭示了激活和抑制变构结合位点之间的相互联系。在此，我们表明，激活结合位点中天然存在的疾病致病突变 Asp(543)Ala 导致 ATP 在抑制变构结合位点的效力增加。激活和抑制变构结合位点之间的相互联系导致酶活性降低，从而导致临床表型。抑制变构结合位点的药理学阻断或激活变构结合位点的高效配体可能对陶赖因病患者具有治疗意义。
