S-adenosylmethionine metabolism buffering is regulated by a decrease in glycine N-methyltransferase via the nuclear ubiquitin-proteasome system.

Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood. In this study, we focused on the stability of SAM levels in the fat body (FB) of Drosophila, which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient deprivation. We found that glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin-proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. The inhibition of Gnmt level reduction by suppression of the nuclear UPS causes starvation tolerance. Thus, the regulation of Gnmt levels through nuclear UPS-mediated reduction helps maintain SAM levels under SAM shortage conditions.