Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Nat Chem Biol. 2012 Oct;8(10):839-47. doi: 10.1038/nchembio.1060.
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.
癌细胞会采用一种代谢程序来增强生物合成并支持细胞增殖。丙酮酸激酶 M2（PKM2）的调节特性会影响癌症中葡萄糖代谢的改变。PKM2 与含磷酸酪氨酸的蛋白质相互作用会抑制酶的活性，并增加糖酵解代谢物的可用性，以支持细胞增殖。这表明高丙酮酸激酶活性可能会抑制肿瘤生长。我们发现，表达具有高组成性活性的丙酮酸激酶同工酶 PKM1，或暴露于已发表的小分子 PKM2 激活剂，均可抑制异种移植肿瘤的生长。结构研究表明，小分子激活剂在亚基相互作用界面结合 PKM2，该位点与内源性激活剂 1,6-二磷酸果糖（FBP）的位点不同。然而，与 FBP 不同的是，激活剂与 PKM2 的结合会促进组成性激活的酶状态，该状态对酪氨酸磷酸化蛋白的抑制作用具有抗性。这些数据支持这样一种观点，即小分子激活 PKM2 可以干扰合成代谢。
