SAICAR activates PKM2 in its dimeric form

• Published in: Biochemistry (Easton) Vol. 55; no. 33; pp. 4731 - 4736
• Main Authors: Yan, Ming, Chakravarthy, Srinivas, Tokuda, Joshua M., Pollack, Lois, Bowman, Gregory D., Lee, Young-Sam
• Format: Journal Article
• Language: English
• Published: 11.08.2016
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.6b00658

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 over 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 SAXS to be a dimer that cannot form tetramer in solution. Although PKM2 G415R binds to FBP, unlike wildtype this PKM2 variant shows no activation by FBP. In contrast, PKM2 G415R is activated by the SAICAR, an endogenous metabolite that we previously showed correlates with increased 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.