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

20 Scopus citations


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
Issue number33
StatePublished - Aug 23 2016

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants R21CA181751 to G.D.B. and Y.-S.L. and R01CA168658 to Y.-S.L. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DEAC02- 06CH11357. The SAXS experiment was supported by Grant 9 P41 GM103622 from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health. Use of the Pilatus 3 1M detector was provided by Grant 1S10OD018090-01 from NIGMS.

Publisher Copyright:
© 2016 American Chemical Society.

ASJC Scopus subject areas

  • Biochemistry


Dive into the research topics of 'Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5′-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form'. Together they form a unique fingerprint.

Cite this