title: Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5'-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form.
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 PKM2(G415R), 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 PKM2(G415R) binds to fructose 1,6-bisphosphate (FBP), unlike the wild type this PKM2 variant shows no activation by FBP. In contrast, PKM2(G415R) 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.
authors.affiliation: T. C. Jenkins Department of Biophysics, Johns Hopkins University , Baltimore, Maryland 21218, United States.|Department of Biology, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Biophysics Collaborative Access Team, Argonne National Laboratory , Argonne, Illinois 60439, United States.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chakravarthy
authors.affiliation: School of Applied and Engineering Physics, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Tokuda
authors.affiliation: School of Applied and Engineering Physics, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Lois
authors.initials: L
authors.lastname: Pollack
authors.affiliation: T. C. Jenkins Department of Biophysics, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Bowman
authors.affiliation: Department of Biology, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Young-Sam
authors.initials: YS
authors.lastname: Lee
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism; D002151:Calorimetry; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation; D011770:Pyruvate Kinase / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism*
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011770:Pyruvate Kinase; C020635:SAICAR