Evidence for an alternative glycolytic pathway in rapidly proliferating cells.
Evidence for an alternative glycolytic pathway in rapidly proliferating cells.
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DOI：
10.1126/science.1188015
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发表时间：
2010-09-17
期刊：
影响因子：
--
通讯作者：
Cantley LC
中科院分区：
文献类型：
--
作者：
Vander Heiden MG;Locasale JW;Swanson KD;Sharfi H;Heffron GJ;Amador-Noguez D;Christofk HR;Wagner G;Rabinowitz JD;Asara JM;Cantley LC
包括癌细胞在内的增殖细胞需要改变新陈代谢，以便有效地将葡萄糖等营养物质纳入生物量。丙酮酸激酶（PKM2）的M2异构体通过有氧糖酵解促进葡萄糖的代谢，并有助于合成代谢。矛盾的是，在快速分裂的癌细胞和组织中，丙酮酸激酶活性的降低伴随着PKM2的表达。我们证明了磷酸烯醇丙酮酸（PEP），细胞中丙酮酸激酶的底物，可以在哺乳动物细胞中作为磷酸供体，因为PEP参与PKM2表达细胞中糖酵解酶磷酸甘油酸变化酶（PGAM1）的磷酸化。我们用质谱分析表明，PEP中的磷酸转移到人PGAM1上的催化组氨酸（His-11）上。该反应发生在PEP的生理浓度下，在缺乏PKM2活性的情况下产生丙酮酸。组氨酸磷酸化的PGAM1的存在与肿瘤细胞系和肿瘤组织中PKM2的表达相关。因此，在表达pkm2的细胞中，丙酮酸激酶活性的降低允许pep依赖的PGAM1的组氨酸磷酸化，并可能提供另一种糖酵解途径，使ATP的产生与pep介导的磷酸转移分离，从而允许高速率的糖酵解，以支持在许多增殖细胞中观察到的合成代谢。
Proliferating cells, including cancer cells, require altered metabolism to efficiently incorporate nutrients such as glucose into biomass. The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of glucose by aerobic glycolysis and contributes to anabolic metabolism. Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. We demonstrate that phosphoenolpyruvate (PEP), the substrate for pyruvate kinase in cells, can act as a phosphate donor in mammalian cells as PEP participates in the phosphorylation of the glycolytic enzyme phosphoglycerate mutase (PGAM1) in PKM2 expressing cells. We used mass spectrometry to show that the phosphate from PEP is transferred to the catalytic histidine (His-11) on human PGAM1. This reaction occurred at physiological concentrations of PEP and produced pyruvate in the absence of PKM2 activity. The presence of histidine-phosphorylated PGAM1 correlated with the expression PKM2 in cancer cell lines and tumor tissues. Thus, decreased pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent histidine phosphorylation of PGAM1, and may provide an alternate glycolytic pathway that decouples ATP production from PEP-mediated phosphotransfer, allowing for the high rate of glycolysis to support anabolic metabolism observed in many proliferating cells.
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影响因子：
8
作者：
Medzihradszky, KF;Phillipps, NJ;Turck, CW
通讯作者：
Turck, CW
DOI：
10.1073/pnas.0710980105
发表时间：
2008-04-22
影响因子：
11.1
作者：
Cho, Jaiesoon;King, Jason S.;Shears, Stephen B.
通讯作者：
Shears, Stephen B.
影响因子：
4.1
作者：
AINSWORTH, S;MACFARLANE, N
通讯作者：
MACFARLANE, N
影响因子：
4.3
作者：
Hohenester, Ulli Martin;Ludwig, Katrin;Koenig, Simone
通讯作者：
Koenig, Simone
影响因子：
7.3
作者：
Hitosugi T;Kang S;Vander Heiden MG;Chung TW;Elf S;Lythgoe K;Dong S;Lonial S;Wang X;Chen GZ;Xie J;Gu TL;Polakiewicz RD;Roesel JL;Boggon TJ;Khuri FR;Gilliland DG;Cantley LC;Kaufman J;Chen J
通讯作者：
Chen J