Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.
Nat Commun. 2024 Aug 29;15(1):7463. doi: 10.1038/s41467-024-51875-9.
Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (HS) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by HS inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism.
大多数癌细胞将其葡萄糖代谢途径从氧化磷酸化重编程为有氧糖酵解以产生能量。通过降低丙酮酸激酶 M2（PKM2）的酶活性，癌细胞获得更多的糖酵解代谢物，用于快速增殖所需的大分子合成。在这里，我们证明硫化氢（HS）通过半胱氨酸（特别是 C326）的巯基化使 PKM2 四聚体不稳定为单体/二聚体，导致 PKM2 酶活性降低和 PKM2 介导的转录激活增加。通过氨基酸突变阻断 C326 上的 PKM2 巯基化可稳定 PKM2 四聚体，晶体结构进一步揭示了 PKM2-C326S 的四聚体组织。癌细胞中的 PKM2-C326S 突变体将葡萄糖代谢重新布线为线粒体呼吸，显著抑制肿瘤生长。在这项工作中，我们证明 HS 对 PKM2 的巯基化使 PKM2 失活，从而促进肿瘤发生，抑制这一过程可能是针对癌症代谢的潜在治疗方法。
