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.
|Number of pages||6|
|State||Published - Aug 23 2016|
Bibliographical noteFunding 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.
© 2016 American Chemical Society.
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