Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Name
Anastasiou et al Nature Chemical Biology.pdf
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15.61 MB
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Author(s)
Yu, Yimin
Israelsen, William James
Mattaini, Katherine Ruth
Fiske, Brian Prescott
Malstrom, Scott E.
Khan, Tahsin M.
Lunt, Sophia Yunkyungkwon
Johnson, Zachary
Davidson, Shawn Michael
Vander Heiden, Matthew G.
Date Issued
October 2012
Journal
Nature Chemical Biology
Publisher
Nature Publishing Group
Citation
Anastasiou, Dimitrios et al. “Pyruvate Kinase M2 Activators Promote Tetramer Formation and Suppress Tumorigenesis.” Nature Chemical Biology 8.10 (2012): 839–847. CrossRef.
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/nchembio.1060
