PKM2 regulates energy sensing and cancer progression through its allosteric regulation

概要

Pyruvate kinases play a pivotal role in metabolism. The M2 isoform of human pyruvate kinase (PKM2) possesses reduced pyruvate kinase activity and can be regulated by allosteric regulation. Natural molecules including FBP and serine are demonstrated to allosterically regulate PKM2 enzymatic activity. PKM2 also harbors non-metabolic functions, as it translocates into the nucleus and serves as a transcriptional co-activator of HIF1α and STAT3. Upregulation of PKM2 was found in many type of cancers. These evidence indicates the oncogenic properties of nuclear PKM2 in cancer progression.

Despite the extensive study done on PKM2, the structure-activity relationship regarding to its allosteric regulation and nuclear function remains elusive. Here, three studies have been carried out. In chapter 1 , I demonstrated that three PKM2 exon-10 mutations result in reduced sensitivity to allosteric effectors and increased nuclear function mediated by KDM8; In chapter 2, I performed the SELEX assay and identified a putative PKM2 - binding DNA motif; Finally, chapter 3 displays the identification of compound X as a novel PKM2 allosteric activator based on structural and biochemical evidence. Collectively, the results provide a mechanistic basis that bridges the allosteric regulation and the nuclear function of PKM2, shedding insights into the new therapeutic anti-cancer strategies.