Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5′-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form

Ming Yan, Srinivas Chakravarthy, Joshua M. Tokuda, Lois Pollack, Gregory D. Bowman, Young Sam Lee

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Human pyruvate kinase isoform M2 (PKM2) is a glycolytic enzyme isoform implicated in cancer. Malignant cancer cells have higher levels of dimeric PKM2, which is regarded as an inactive form of tetrameric pyruvate kinase. This perceived inactivity has fueled controversy about how the dimeric form of pyruvate kinase might contribute to cancer. Here we investigate enzymatic properties of PKM2G415R, a variant derived from a cancer patient, which we show by size-exclusion chromatography and small-angle X-ray scattering to be a dimer that cannot form a tetramer in solution. Although PKM2G415R binds to fructose 1,6-bisphosphate (FBP), unlike the wild type this PKM2 variant shows no activation by FBP. In contrast, PKM2G415R is activated by succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5′-phosphate (SAICAR), an endogenous metabolite that we previously showed correlates with an increased level of cell proliferation and promotes protein kinase activity of PKM2. Our results demonstrate an important and unexpected enzymatic activity of the PKM2 dimer that likely has a key role in cancer progression.

Original languageEnglish
Pages (from-to)4731-4736
Number of pages6
JournalBiochemistry
Volume55
Issue number33
DOIs
StatePublished - Aug 23 2016

Bibliographical note

Publisher Copyright:
© 2016 American Chemical Society.

ASJC Scopus subject areas

  • Biochemistry

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