S-adenosylmethionine metabolism buffering is regulated by glycine N-methyltransferase decrease via 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. Furthermore, the nuclear accumulation of Gnmt with age disrupts the mechanism that maintains a stable SAM level. Thus, the regulation of Gnmt levels through nuclear UPS-mediated degradation helps maintain SAM levels under SAM shortage conditions and during aging.

Significance Statement

S-adenosylmethionine (SAM) metabolism is crucial for diverse functions, which are mediated through methylation process. Although the feedback regulation of SAM production has been explored extensively, our understanding of the mechanism behind SAM consumption remains incomplete. Constant levels of SAM have been observed in Drosophila fat bodies even under conditions of SAM shortage, including nutrient deficiency and inhibition of SAM synthesis. SAM levels are controlled by the degradation of glycine N-methyltransferase (Gnmt), a cytosolic SAM-consuming enzyme, via the nuclear ubiquitin-proteasome system under conditions of SAM shortage. Additionally, the inhibition of Gnmt degradation by suppression of the nuclear UPS causes starvation tolerance. Considering that SAM accumulation promotes energy expenditure in vivo , the starvation-dependent mechanism of Gnmt degradation is important for energy homeostasis.