Metabolic Crosstalk between Folate Metabolism and Glycolysis via Pyruvate Kinase Modulation

Pyruvate kinase catalyzes the final rate-limiting step of glycolysis, generating pyruvate and ATP from phosphoenolpyruvate and ADP. Among its isozymes, pyruvate kinase muscle isoform M2 (PKM2) is highly expressed in highly proliferative tissues, including embryonic and adult stem cells and tumors. PKM2 has emerged as a central regulator in cancer metabolism due to its complex allosteric control by various metabolites. In parallel, one-carbon metabolism through the folate cycle supports essential cellular functions including amino acid homeostasis, methylation reactions, redox defense, and nucleotide biosynthesis: operations that are key for rapidly proliferating cells.

We have discovered that some folate metabolites function as PKM2 activators, revealing a hitherto unknown signaling axis between one-carbon metabolism and glycolysis. We are investigating whether this activation reflects a coordinated regulatory mechanism in proliferating cells, in which cytosolic folate metabolites dynamically modulate lower glycolysis to redirect intermediates toward serine synthesis, a major source of one-carbon units.