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

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. 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 proliferation1. 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 glycine2. 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.