A key player in metabolism, the folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly converts the amino acid serine into another amino acid, glycine, releasing a tetrahydrofolate-bound one-carbon unit. This process plays a critical role in development, the immune system and in cancer: SHMT2 is a driver of both cancer cell proliferation and T cell activation. A team led by Ludwig Princeton Director Joshua Rabinowitz reported in Cell Metabolism in January that the biosynthesis of serine and glycine is not sensitive to dietary levels of these amino acids in mice and that their homeostasis—or appropriate systemic balance—is maintained by glycine consumption in the liver, where the folate pathway runs in reverse to generate serine. Targeting this process in mice by the pharmacological inhibition of SHMT1/2 or by the deletion of these enzymes in the liver led to an 8-fold surge in systemic levels of glycine. Josh and his colleagues showed that when there is an insufficient supply of glycine or serine, mice adjust by modulating their consumption rather than stepping up their production. Isotope labeling revealed that the serine produced from glycine by the liver is converted into pyruvate and burned to produce energy via the TCA cycle, a core process of normal cellular respiration. The findings are of considerable relevance to cancer therapy as serine/glycine-free diets have anticancer activity in mice and are currently being tested in humans.
Glycine homeostasis requires reverse SHMT flux
Cell Metabolism, 2024 January 2