Sensing and Signaling of Methionine Metabolism

Availability of the amino acid methionine shows remarkable effects on the physiology of individual cells and whole organisms. For example, most cancer cells, but not normal cells, are hyper dependent on high flux through metabolic pathways connected to methionine, and diets restricted for methionine increase healthy lifespan in model organisms. Methionine's impact on physiology goes beyond its role in initiation of translation and incorporation in proteins. Many of its metabolites have a major influence on cellular functions including epigenetic regulation, maintenance of redox balance, polyamine synthesis, and phospholipid homeostasis. As a central component of such essential pathways, cells require mechanisms to sense methionine availability. When methionine levels are low, cellular response programs induce transcriptional and signaling states to remodel metabolic programs and maintain methionine metabolism. In addition, an evolutionary conserved cell cycle arrest is induced to ensure cellular and genomic integrity during methionine starvation conditions. Methionine and its metabolites are critical for cell growth, proliferation, and development in all organisms. However, mechanisms of methionine perception are diverse. Here we review current knowledge about mechanisms of methionine sensing in yeast and mammalian cells, and will discuss the impact of methionine imbalance on cancer and aging.