Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
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丙酮酸激酶M2激活剂促进四聚体形成并抑制肿瘤发生。
DOI：
10.1038/nchembio.1060
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发表时间：
2012-10
影响因子：
14.8
通讯作者：
Heiden, Matthew G. Vander
中科院分区：
文献类型：
--
作者：
Anastasiou, Dimitrios;Yu, Yimin;Israelsen, William J.;Jiang, Jian-Kang;Boxer, Matthew B.;Hong, Bum Soo;Tempel, Wolfram;Dimov, Svetoslav;Shen, Min;Jha, Abhishek;Yang, Hua;Mattaini, Katherine R.;Metallo, Christian M.;Fiske, Brian P.;Courtney, Kevin D.;Malstrom, Scott;Khan, Tahsin M.;Kung, Charles;Skoumbourdis, Amanda P.;Veith, Henrike;Southall, Noel;Walsh, Martin J.;Brimacombe, Kyle R.;Leister, William;Lunt, Sophia Y.;Johnson, Zachary R.;Yen, Katharine E.;Kunii, Kaiko;Davidson, Shawn M.;Christofk, Heather R.;Austin, Christopher P.;Inglese, James;Harris, Marian H.;Asara, John M.;Stephanopoulos, Gregory;Salituro, Francesco G.;Jin, Shengfang;Dang, Lenny;Auld, Douglas S.;Park, Hee-Won;Cantley, Lewis C.;Thomas, Craig J.;Heiden, Matthew G. Vander
癌细胞参与代谢程序以增强生物合成并支持细胞增殖。丙酮酸激酶M2（PKM 2）的调节特性影响癌症中葡萄糖代谢的改变。PKM 2与含磷酸酪氨酸的蛋白质的相互作用抑制酶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以抑制肿瘤生长。我们表明，表达PKM 1，丙酮酸激酶亚型与高组成型活性，或暴露于公开的小分子PKM 2激活剂抑制异种移植肿瘤的生长。结构研究表明，小分子激活剂结合PKM 2的亚基相互作用界面，一个网站不同的内源性激活剂果糖-1，6-二磷酸（FBP）。然而，与FBP不同的是，激活剂与PKM 2的结合促进了对酪氨酸磷酸化蛋白的抑制具有抗性的组成型活性酶状态。这些数据支持PKM 2的小分子激活可以干扰合成代谢的观点。
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. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases 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 inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site 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.
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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
2.9
作者：
ASHIZAWA, K;MCPHIE, P;CHENG, SY
通讯作者：
CHENG, SY
影响因子：
2.7
作者：
Jiang, Jian-kang;Boxer, Matthew B.;Vander Heiden, Matthew G.;Shen, Min;Skoumbourdis, Amanda P.;Southall, Noel;Veith, Henrike;Leister, William;Austin, Christopher P.;Park, Hee Won;Inglese, James;Cantley, Lewis C.;Auld, Douglas S.;Thomas, Craig J.
通讯作者：
Thomas, Craig J.
影响因子：
4.8
作者：
Hoshino, Akemi;Hirst, John A.;Fujii, Hodaka
通讯作者：
Fujii, Hodaka
影响因子：
64.8
作者：
Metallo, Christian M.;Gameiro, Paulo A.;Bell, Eric L.;Mattaini, Katherine R.;Yang, Juanjuan;Hiller, Karsten;Jewell, Christopher M.;Johnson, Zachary R.;Irvine, Darrell J.;Guarente, Leonard;Kelleher, Joanne K.;Vander Heiden, Matthew G.;Iliopoulos, Othon;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory