科學(xué)家近日發(fā)現(xiàn)，調(diào)節(jié)代謝的小分子活化物質(zhì)能阻礙腫瘤的生長(zhǎng),，近期的《自然—化學(xué)生物學(xué)》雜志刊登了這一研究,。這或?qū)⒂兄诎┌Y療法的開發(fā)。
在糖酵解過(guò)程中,，丙酮酸激酶負(fù)責(zé)實(shí)現(xiàn)最后一步代謝過(guò)程,，即將葡萄糖轉(zhuǎn)化為能量以及對(duì)細(xì)胞有重要作用的合成代謝物。丙酮酸激酶分兩種：PKM1和PKM2,，其中PKM1的活性較大,，而PKM2轉(zhuǎn)變后的活性能與腫瘤細(xì)胞相符合。
Matthew Vander Heiden等人報(bào)告了一類與PKM2發(fā)生特異結(jié)合并促使其產(chǎn)生活性的小分子活化物質(zhì)通過(guò)阻礙腫瘤生長(zhǎng)的方式使腫瘤細(xì)胞的代謝發(fā)生改變,。這些活化物質(zhì)與PKM2中的新發(fā)現(xiàn)的位點(diǎn)相結(jié)合,，使得PKM2對(duì)一類負(fù)反饋回路產(chǎn)生抗性——該類負(fù)反饋回路可使促生長(zhǎng)代謝物產(chǎn)生。對(duì)PKM2的持續(xù)激活會(huì)切斷腫瘤細(xì)胞中合成代謝養(yǎng)分的供應(yīng),。PKM2的活化物質(zhì)還能讓腫瘤細(xì)胞對(duì)氧化應(yīng)激過(guò)敏,，這引導(dǎo)出了一種潛在新療法的開發(fā)：通過(guò)活化PKM2并結(jié)合觸發(fā)氧化應(yīng)激的方式,，實(shí)現(xiàn)殺死腫瘤細(xì)胞的目的。（生物谷Bioon.com）
doi:10.1038/nchembio.1060
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Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Dimitrios Anastasiou,Yimin Yu,William J Israelsen,Jian-Kang Jiang,Matthew B Boxer,Bum Soo Hong,Wolfram Tempel,Svetoslav Dimov,Min Shen,Abhishek Jha,Hua Yang,Katherine R Mattaini,Christian M Metallo,Brian P Fiske,Kevin D Courtney,Scott Malstrom,Tahsin M Khan,Charles Kung,Amanda P Skoumbourdis,Henrike Veith,Noel Southall,Martin J Walsh,Kyle R Brimacombe,William Leister,Sophia Y Lunt et al.
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.
