Serine is a natural ligand and allosteric activator of pyruvate kinase M2

• Published in: Nature (London) Vol. 491; no. 7424; pp. 458 - 462
• Main Authors: Chaneton, Barbara, Hillmann, Petra, Zheng, Liang, Martin, Agnès C. L., Maddocks, Oliver D. K., Chokkathukalam, Achuthanunni, Coyle, Joseph E., Jankevics, Andris, Holding, Finn P., Vousden, Karen H., Frezza, Christian, O’Reilly, Marc, Gottlieb, Eyal
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.11.2012; Nature Publishing Group
• Subjects: 631/443/319; 631/67; 631/80/86; 631/92/60; Biological and medical sciences; Biosynthesis; Cancer; Carcinogenesis, carcinogens and anticarcinogens; Cell Line, Tumor; Cell Proliferation; Enzyme Activation - drug effects; Enzyme Activators - pharmacology; Enzymes; General aspects; Glucose - metabolism; Glycine - metabolism; Glycine - pharmacology; Humanities and Social Sciences; Humans; Kinases; letter; Ligands; Ligands (Biochemistry); Medical sciences; Metabolites; multidisciplinary; Observations; Phosphotransferases; Physiological aspects; Properties; Proteins; Pyruvate kinase; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Pyruvic Acid - metabolism; Recombinant Proteins - metabolism; Science; Serine; Serine - metabolism; Serine - pharmacology; Tumors; United Kingdom; Human; Cell proliferation; Pyruvate kinase; Enzyme; Isozyme; Ligand; Transferases; Serine; Malignant tumor; Allosteric activation; Carcinogenesis; Cancerology; Aminoacid; Cancer
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11540

The M2 isoform of pyruvate kinase (PKM2) is a key glycolytic enzyme that is overexpressed in cancer cells; here, serine is shown to bind to and directly activate PKM2, and the resulting reduction in enzyme activity under serine-deprivation conditions is shown to lead to the diversion of glucose-derived carbon to promote serine biosynthesis required for cell proliferation. Serine biosynthesis linked to glycolysis The M2 isoform of pyruvate kinase (PKM2) is a key enzyme in glycolysis, and is expressed in many proliferating cells including cancer cells. Using biochemical, structural and cell-based experiments, these authors show that, as has been previously suggested, serine directly binds to and activates PKM2. Under conditions of serine depletion, the resulting reduction in PKM2 activity is shown to divert pyruvate into mitochondrial metabolism, thereby promoting serine biosynthesis, which is required for cell proliferation. This work clarifies the relationship between glucose and amino acid metabolism, demonstrating a mechanism whereby glucose-derived carbon is utilized for serine biosynthesis or energy production. Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation 1 . Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine 2 . Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation.