N-terminal methionine removal and methionine metabolism in Saccharomyces cerevisiae

Methionine aminopeptidase (MetAP) catalyzes removal of the initiator methionine from nascent polypeptides. In eukaryotes, there are two forms of MetAP, type 1 and type 2, whose combined activities are essential, but whose relative intracellular roles are unclear. Methionine metabolism is an important aspect of cellular physiology, involved in oxidative stress, methylation, and cell cycle. Due to the potential of MetAP activity to provide a methionine salvage pathway, we evaluated the relationship between methionine metabolism and MetAP activity in Saccharomyces cerevisiae. We provide the first demonstration that yeast MetAP1 plays a significant role in methionine metabolism, namely, preventing premature activation of MET genes through MetAP function in methionine salvage. Interestingly, in cells lacking MetAP1, excess methionine dramatically inhibits cell growth. Growth inhibition is independent of the ability of methionine to repress MET genes and does not result from inhibition of synthesis of another metabolite, rather it results from product inhibition of MetAP2. Inhibition by methionine is selective for MetAP2 over MetAP1. These results provide an explanation for the previously observed dominance of MetAP1 in terms of N-terminal processing and cell growth in yeast. Additionally, differential regulation of the two isoforms may be indicative of different intracellular roles for the two enzymes.