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Science 329 (5998): 1492-1499

Copyright © 2010 by the American Association for the Advancement of Science

Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells

Matthew G. Vander Heiden,1,2,3,* Jason W. Locasale,2,3 Kenneth D. Swanson,2 Hadar Sharfi,2 Greg J. Heffron,4 Daniel Amador-Noguez,5 Heather R. Christofk,2 Gerhard Wagner,4 Joshua D. Rabinowitz,5 John M. Asara,2 Lewis C. Cantley2,3,{dagger}

Abstract: 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 because 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 (His11) 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 of 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 adenosine triphosphate production from PEP-mediated phosphotransfer, allowing for the high rate of glycolysis to support the anabolic metabolism observed in many proliferating cells.

1 Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
2 Beth Israel Deaconess Medical Center, Division of Signal Transduction and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
4 Department of Biological Chemistry and Molecular Pharmacology; Harvard Medical School, Boston, MA 02115, USA.
5 Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.

* Present address: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

{dagger} To whom correspondence should be addressed. E-mail: lewis_cantley{at}

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