Delobelle Quentin, Inizan Théo Jaffrelot, Adjoua Olivier, Lagardère Louis, Célerse Frédéric, Maréchal Vincent, Piquemal Jean-Philip
Centre de Recherche Saint-Antoine - Team "Biologie et Thérapeutique du Cancer", UMRS 938 INSERM, Paris, France.
Sorbonne Université, CNRS, Laboratoire de Chimie Théorique, UMR 7616, 75005, Paris, France.
Chemistry. 2025 Apr 4;31(20):e202402534. doi: 10.1002/chem.202402534. Epub 2025 Mar 15.
Glucose metabolism plays a pivotal role in physiological processes and cancer growth. The final stage of glycolysis, converting phosphoenolpyruvate (PEP) into pyruvate, is catalyzed by the pyruvate kinase (PK) enzyme. Whereas PKM1 is mainly expressed in cells with high energy requirements, PKM2 is preferentially expressed in proliferating cells, including tumor cells. Structural analysis of PKM1 and PKM2 is essential to design new molecules with antitumoral activity. To understand their structural dynamics, we performed extensive high-resolution molecular dynamics (MD) simulations using adaptive sampling techniques coupled to the polarizable AMOEBA force field. Performing more than 6 μs of simulation, we considered all oligomerization states of PKM2 and propose structural insights for PKM1 to further study the PKM2-specific allostery. We focused on key sites including the active site and the natural substrate Fructose Bi-Phosphate (FBP) fixation pocket. Additionally, we present the first MD simulation of biologically active PKM1 and uncover important similarities with its PKM2 counterpart bound to FBP. We also analysed TEPP-46's fixation, a pharmacological activator binding a different pocket, on PKM2 and highlighted the structural differences and similarities compared to PKM2 bound to FBP. Finally, we determined potential new cryptic pockets specific to PKM2 for drug targeting.
葡萄糖代谢在生理过程和癌症生长中起着关键作用。糖酵解的最后阶段，即将磷酸烯醇丙酮酸（PEP）转化为丙酮酸，由丙酮酸激酶（PK）催化。PKM1主要在能量需求高的细胞中表达，而PKM2则优先在包括肿瘤细胞在内的增殖细胞中表达。PKM1和PKM2的结构分析对于设计具有抗肿瘤活性的新分子至关重要。为了了解它们的结构动力学，我们使用与可极化AMOEBA力场耦合的自适应采样技术进行了广泛的高分辨率分子动力学（MD）模拟。通过进行超过6微秒的模拟，我们考虑了PKM2的所有寡聚化状态，并为PKM1提出了结构见解，以进一步研究PKM2特异性变构。我们关注了包括活性位点和天然底物果糖二磷酸（FBP）固定口袋在内的关键位点。此外，我们展示了生物活性PKM1的首次MD模拟，并揭示了其与结合FBP的PKM2对应物的重要相似之处。我们还分析了TEPP - 46在PKM2上的固定情况，TEPP - 46是一种结合不同口袋的药理激活剂，并强调了与结合FBP的PKM2相比的结构差异和相似之处。最后，我们确定了PKM2特有的潜在新隐秘口袋用于药物靶向。
